METHODS OF DIAGNOSING AND TREATING CANCER

TECHNICAL FIELD

This invention relates to methods of genetics, diagnostics, and pharmacogenetics.

BACKGROUND

Tropomyosin-related kinase (TRK) is a receptor tyrosine kinase family of neurotrophin receptors that are found in multiple tissues types. Three members of the TRK proto-oncogene family have been described: TrkA, TrkB, and TrkC, coded by the NTRK1, NTRK2, and NTRK3 genes, respectively. The TRK receptor family is involved in neuronal development, including the growth and function of neuronal synapses, memory development, and maintenance, and the protection of neurons after ischemia or other types of injury (Nakagawara, Cancer Lett. 169:107-114, 2001).

TRK was originally identified from a colorectal cancer as an oncogene fusion containing 5′ sequences from tropomyosin-3 (TPM3) gene and the kinase domain encoded by the 3′ region of the neurotrophic tyrosine kinase, receptor, type 1 gene (NTRK1) (Pulciani et al., Nature 300:539-542, 1982; Martin-Zanca et al., Nature 319:743-748, 1986). TRK gene fusions follow the well-established paradigm of other oncogenic fusions, such as those involving ALK and ROS1 that have been shown to drive the growth of tumors and can be successfully inhibited in the clinic by targeted drugs (Shaw et al., New Engl. J. Med. 371:1963-1971, 2014; Shaw et al., New Engl. J. Med. 370:1189-1197, 2014). Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways such as MAPK and AKT (Vaishnavi et al., Cancer Discov. 5:25-34, 2015). Numerous oncogenic rearrangements involving NTRK1 and its related TRK family members NTRK2 and NTRK3 have been discovered (Vaishnavi et al., Cancer Disc. 5:25-34, 2015; Vaishnavi et al., Nature Med. 19:1469-1472, 2013). Although there are numerous different 5′ gene fusion partners identified, all share an in-frame, intact TRK kinase domain. A variety of different Trk inhibitors have been developed to treat cancer (see, e.g., U.S. Patent Application Publication No. 62/080,374, International Application Publication Nos. WO 11/006074, WO 11/146336, WO 10/033941, and WO 10/048314, and U.S. Pat. Nos. 8,933,084, 8,791,123, 8,637,516, 8,513,263, 8,450,322, 7,615,383, 7,384,632, 6,153,189, 6,027,927, 6,025,166, 5,910,574, 5,877,016, and 5,844,092).

SUMMARY

The present invention is based on the discovery that a biopsy samples from subjects having a variety of different cancers include a cancer cell that has at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising a mutation at one or more amino acid position(s) (e.g., a substitution or a deletion). In view of this discovery, provided herein are methods of treating a subject having a cancer that include administering to a subject identified as having a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein) a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein or known in the art), methods of selecting a treatment including a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein or known in the art) for a subject identified as having a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), methods of determining the likelihood that a subject having a cancer will have a positive response to a treatment based upon whether the subject has a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein or known in the art) in a subject having a cancer based upon whether the subject has a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) based upon whether the subject has a cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), and methods of assisting in the diagnosis of cancer (e.g., any of the cancers described herein) in a subject based upon whether the subject has a cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein).

Also provided herein are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689; and administering to the identified subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

Also provided herein are methods of treating a subject identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), that includes administering to the subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

Also provided are methods of treating a subject identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutations in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, the method including administering to the subject a therapeutically effective amount of a Trk inhibitor.

Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and selecting a treatment including a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for the identified subject.

Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689; and selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for the identified subject.

Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include selecting a treatment including a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for a subject identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein).

Some embodiments of these methods further include administering a therapeutically effective amount of the selected treatment to the identified subject. Some embodiments of these methods further include recording the selected treatment in the identified subject's clinical record (e.g., a computer readable medium).

Also provided are methods of determining the likelihood that a subject having a cancer will have a positive response to treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining whether a cancer cell in a sample obtained from the subject (e.g., a biopsy sample) has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689; and determining that a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided are methods of determining the likelihood that a subject having cancer (e.g., any of the cancers described herein) will have a positive response to treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining that a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided are methods of determining the likelihood that a subject having cancer (e.g., any of the cancers described herein) will have a positive response to treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining that a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Some embodiments of these methods further include administering a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) to a subject determined to have an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided are methods of predicting the efficacy of a Trk inhibitor (e.g., any of so the Trk inhibitors described herein) in a subject having cancer (e.g., any of the cancers described herein) that include determining whether a cancer cell in a sample obtained from the subject (e.g., a biopsy sample) has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein).

Also provided are methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) in a subject having a cancer (e.g., any of the cancers described herein) that include determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein).

Also provided are methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) in a subject having a cancer (e.g., any of the cancers described herein) that include determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689.

In some embodiments of any of these methods, the subject is previously identified or diagnosed as having the cancer.

In some embodiments, the step of identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA. TrkB, and/or TrkC described herein), comprises performing an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene in a cancer cell in a sample from the subject.

In some embodiments, the step of identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, comprises performing an assay to determine the presence of the at least one point mutation in a NTRK2 gene in a cancer cell in a sample from the subject.

In some embodiments of these methods, the assay is selected from the group of: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, a single strand conformational polymorphism assay, a molecular beacon assay, a dynamic hybridization assay, a PCR-based assay, and denaturing high performance liquid chromatography. In some embodiments of these methods, the assay includes sequencing a segment of the NTRK1, NTRK2, and/or NTRK3 gene comprising the at least one point mutation.

In any of the methods described herein, the Trk inhibitor a crystalline form of the compound of Formula I:

embedded image

or a hydrogen sulfate salt thereof.

Also provided are methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) as having an increased likelihood of developing a cancer.

Also provided are methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, and identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, as having an increased likelihood of developing a cancer.

Also provided are methods of determining a subject's risk of developing a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) as having an increased likelihood of developing a cancer.

Also provided are methods of determining a subject's risk of developing a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, as having an increased likelihood of developing a cancer.

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA. TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), has an increased likelihood of having a cancer.

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, and determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, has an increased likelihood of having a cancer.

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), has an increased likelihood of having a cancer.

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, has an increased likelihood of having a cancer.

In some embodiments of these methods, the subject is identified as having been exposed to a significant level of carcinogen(s). In some embodiments of these methods, the subject is suspected of having a cancer. In some embodiments of these methods, the subject has one or more symptoms of cancer.

In any of the methods described herein, the cancer is selected from the group of: adenocarcinoma, adrenal gland cortical carcinoma, adrenal gland neuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bile duct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acute myelocytic, bone marrow lymph proliferative disease, bone marrow multiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma, brain medulloblastoma, brain meningioma, brain oligodendroglioma, breast adenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma in situ, breast invasive ductal carcinoma, breast invasive lobular carcinoma, breast metaplastic carcinoma, cervix neuroendocrine carcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, esophagus and stomach carcinoma, eye intraocular melanoma, eye intraocular squamous cell carcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophageal junction adenocarcinoma, head and neck adenoid cystic carcinoma, head and neck carcinoma, head and neck neuroblastoma, head and neck squamous cell carcinoma, kidney chromophore carcinoma, kidney medullary carcinoma, kidney renal cell carcinoma, kidney renal papillary carcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma, kidney carcinoma, leukemia lymphocytic, leukemia lymphocytic chronic, liver cholangiocarcinoma, liver hepatocellular carcinoma, liver carcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrine carcinoma, lung non-small cell lung carcinoma, lung sarcoma, lung sarcomatoid carcinoma, lung small cell carcinoma, lung small cell undifferentiated carcinoma, lung squamous cell carcinoma, upper aerodigestive tract squamous cell carcinoma, upper aerodigestive tract carcinoma, lymph node lymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma, lymph node lymphoma mediastinal B-cell, lymph node lymphoma plasmablastic lung adenocarcinoma, lymphoma follicular lymphoma, lymphoma, non-Hodgkins, nasopharynx and paranasal sinuses undifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovary clear cell carcinoma, ovary epithelial carcinoma, ovary granulosa cell tumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductal adenocarcinoma, pancreas neuroendocrine carcinoma, peritoneum mesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma, pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma, rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexal carcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cell carcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma, small intestine gastrointestinal stromal tumors (GISTs), large intestine/colon carcinoma, large intestine adenocarcinoma, soft tissue angiosarcoma, soft tissue Ewing sarcoma, soft tissue hemangioendothelioma, soft tissue inflammatory myofibroblastic tumor, soft tissue leiomosarcoma, soft tissue liposarcoma, soft tissue neuroblastoma, soft tissue paraganglioma, soft tissue perivascular epitheliod cell tumor, soft tissue sarcoma, soft tissue synovial sarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type, stomach adenocarcinoma intestinal type, stomach adenocarcinoma intestinal type, stomach leionmosarcoma, thymus carcinoma, thymus thymoma lymphocytic, thyroid papillary carcinoma, unknown primary adenocarcinoma, unknown primary carcinoma, unknown primary malignant neoplasm, lymphoid neoplasm, unknown primary melanoma, unknown primary sarcomatoid carcinoma, unknown primary squamous cell carcinoma, unknown undifferentiated neuroendocrine carcinoma, unknown primary undifferentiated small cell carcinoma, uterus carcinosarcoma, uterus endometrial adenocarcinoma, uterus endometrial adenocarcinoma endometrioid, uterus endometrial adenocarcinoma papillary serous, and uterus leiomyosarcoma.

In some embodiments of these methods, the step of determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) includes performing an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRk3 gene in a cell in the sample.

In some embodiments of these methods, the step of determining whether a cell in a sample obtained from the subject has at least one point (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689, includes performing an assay to determine the presence of the at least one point mutation in a NTRK2 gene in a cell in the sample.

In some embodiments, the assay is selected from the group of: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, a single strand conformational polymorphism assay, a molecular beacon assay, a dynamic hybridization assay, a PCR-based assay, denaturing high performance liquid chromatography. In some embodiments, the assay includes sequencing a segment of the NTRK1, NTRK2, and/or NTRK3 gene including the at least one point mutation.

Some methods further include confirming the diagnosis of a cancer in a subject determined to have an increased likelihood of having a cancer.

In some embodiments of any of the methods claims described herein, the TrkB protein comprises a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group of: M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M.

Also provided are kits including one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) probes that each specifically hybridize to a segment of a NTRK1, NTRK2, or NTRK3 gene that encodes a mutation at one of the amino acid positions in TrkA, TrkB, or TrkC (e.g., any of the specific mutations in TrkA, TrkB, or TrkC described herein).

Also provided are kits including one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) probes that each specifically hybridize to a segment of a NTRK3 gene that encodes a mutation at one of amino acid positions 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 in TrkB protein. In some examples, the kit includes one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) probes that each specifically hybridize to a segment of a NTRK3 gene that encodes a mutation selected from the group of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M in TrkB protein.

In some embodiments of the kits, the one or more probes are labeled with a detectable probe. In some embodiments of the kits, the one or more probes are covalently attached to a substrate (e.g., a film, a plate, or a bead).

Also provided herein are methods of treating a subject having a cancer that include: (a) identifying a subject having a cancer cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805, and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) administering to the identified subject a therapeutically effective amount of a Trk inhibitor.

Also provided herein are methods of treating a subject identified as having a cancer cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810, the method comprising administering to the subject a therapeutically effective amount of a Trk inhibitor.

Also provided herein are methods of selecting a treatment for a subject having a cancer that include: (a) identifying a subject having a cancer cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor for the identified subject.

Also provided herein are methods of selecting a treatment for a subject having a cancer that include selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor for a subject identified as having a cancer cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810.

Also provided herein are methods of determining the likelihood that a subject having a cancer will have a positive response to treatment with a Trk inhibitor that include: (a) determining whether a cancer cell in a sample obtained from the subject has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) determining that a subject having a cancer cell that has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene, has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided herein are methods of determining the likelihood that a subject having cancer will have a positive response to treatment with a Trk inhibitor that include: determining that a subject having a cancer cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of: 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810, has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided herein are methods of predicting the efficacy of a Trk inhibitor in a subject having cancer that include: (a) determining whether a cancer cell in a sample obtained from the subject has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene.

Also provided are methods of predicting the efficacy of a Trk inhibitor in a subject having cancer that include determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810.

In some embodiments of any of the methods described herein, the cancer is selected from the group of: adenocarcinoma, adrenal gland cortical carcinoma, adrenal gland neuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bile duct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acute myelocytic, bone marrow lymph proliferative disease, bone marrow multiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma, brain medulloblastoma, brain meningioma, brain oligodendroglioma, breast adenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma in situ, breast invasive ductal carcinoma, breast invasive lobular carcinoma, breast metaplastic carcinoma, cervix neuroendocrine carcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, esophagus and stomach carcinoma, eye intraocular melanoma, eye intraocular squamous cell carcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophageal junction adenocarcinoma, head and neck adenoid cystic carcinoma, head and neck carcinoma, head and neck neuroblastoma, head and neck squamous cell carcinoma, kidney chromophore carcinoma, kidney medullary carcinoma, kidney renal cell carcinoma, kidney renal papillary carcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma, kidney carcinoma, leukemia lymphocytic, leukemia lymphocytic chronic, liver cholangiocarcinoma, liver hepatocellular carcinoma, liver carcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrine carcinoma, lung non-small cell lung carcinoma, lung sarcoma, lung sarcomatoid carcinoma, lung small cell carcinoma, lung small cell undifferentiated carcinoma, lung squamous cell carcinoma, upper aerodigestive tract squamous cell carcinoma, upper aerodigestive tract carcinoma, lymph node lymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma, lymph node lymphoma mediastinal B-cell, lymph node lymphoma plasmablastic lung adenocarcinoma, lymphoma follicular lymphoma, lymphoma, non-Hodgkins, nasopharynx and paranasal sinuses undifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovary clear cell carcinoma, ovary epithelial carcinoma, ovary granulosa cell tumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductal adenocarcinoma, pancreas neuroendocrine carcinoma, peritoneum mesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma, pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma, rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexal carcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cell carcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma, small intestine gastrointestinal stromal tumors (GISTs), large intestine/colon carcinoma, large intestine adenocarcinoma, soft tissue angiosarcoma, soft tissue Ewing sarcoma, soft tissue hemangioendothelioma, soft tissue inflammatory myofibroblastic tumor, soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissue neuroblastoma, soft tissue paraganglioma, soft tissue perivascular epitheliod cell tumor, soft tissue sarcoma, soft tissue synovial sarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type, stomach adenocarcinoma intestinal type, stomach adenocarcinoma intestinal type, stomach leiomyosarcoma, thymus carcinoma, thymus thymoma lymphocytic, thyroid papillary carcinoma, unknown primary adenocarcinoma, unknown primary carcinoma, unknown primary malignant neoplasm, lymphoid neoplasm, unknown primary melanoma, unknown primary sarcomatoid carcinoma, unknown primary squamous cell carcinoma, unknown undifferentiated neuroendocrine carcinoma, unknown primary undifferentiated small cell carcinoma, uterus carcinosarcoma, uterus endometrial adenocarcinoma, uterus endometrial adenocarcinoma endometrioid, uterus endometrial adenocarcinoma papillary serous, and uterus leiomyosarcoma.

In some embodiments of any of the methods described herein, the subject is previously identified or diagnosed as having the cancer. In some embodiments of any of the methods described herein, the step of identifying a subject having a cancer cell that has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene includes performing an assay to determine the presence of the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene, in a cancer cell in a sample from the subject. In some embodiments of any of the methods described herein, the assay is selected from the group of: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, a single strand conformational polymorphism assay, a molecular beacon assay, a dynamic hybridization assay, a PCR-based assay, and denaturing high performance liquid chromatography. In some embodiments of any of the methods described herein, the assay includes sequencing a segment of the NTRK1 gene comprising the at least one point mutation, a segment of the NTRK2 gene comprising the at least one point mutation, and/or a segment of the NTRK3 gene comprising the at least one point mutation.

In some embodiments of any of the methods described herein, the Trk inhibitor a crystalline form of the compound of Formula I:

embedded image

or a hydrogen sulfate salt thereof.

Some embodiments of any of the methods described herein further include: administering a therapeutically effective amount of the selected treatment to the identified subject. Some embodiments of any of the methods described herein further include: recording the selected treatment in the identified subject's clinical record (e.g., a computer readable medium). Some embodiments of any of the methods described herein further include: administering a therapeutically effective amount of a Trk inhibitor to a subject determined to have an increased likelihood of having a positive response to treatment with a Trk inhibitor.

Also provided herein are methods of determining a subject's risk for developing a cancer that include: (a) determining whether a cell in a sample obtained from the subject has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) identifying a subject having a cell that has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene as having an increased likelihood of developing a cancer.

Also provided herein are methods of determining a subject's risk for developing a cancer that include identifying a subject having a cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of: 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810, as having an increased likelihood of developing a cancer.

Also provided herein are methods of assisting in the diagnosis of a cancer in a subject that include: (a) determining whether a cell in a sample obtained from the subject has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810; and (b) determining that a subject having a cell that has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene, has an increased likelihood of having a cancer.

Also provided are methods of assisting in the diagnosis of a cancer in a subject that include determining that a subject having a cell that has: at least one point mutation in a NTRK1 gene that results in the expression of a TrkA protein including a mutation at one or more amino acid position(s) selected from the group of 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750; at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more amino acid position(s) selected from the group of 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805; and/or at least one point mutation in a NTRK3 gene that results in the expression of a TrkC protein including a mutation at one or more amino acid position(s) selected from the group of 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810, has an increased likelihood of having a cancer.

In some embodiments of any of the methods described herein, the subject is identified as having been exposed to a significant level of carcinogen(s). In some embodiments of any of the methods described herein, the subject is suspected of having a cancer. In some embodiments of any of the methods described herein, the subject has one or more symptoms of cancer. In some embodiments of any of the methods described herein, the cancer is selected from the group of: adenocarcinoma, adrenal gland cortical carcinoma, adrenal gland neuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bile duct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acute myelocytic, bone marrow lymph proliferative disease, bone marrow multiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma, brain medulloblastoma, brain meningioma, brain oligodendroglioma, breast adenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma in situ, breast invasive ductal carcinoma, breast invasive lobular carcinoma, breast metaplastic carcinoma, cervix neuroendocrine carcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, esophagus and stomach carcinoma, eye intraocular melanoma, eye intraocular squamous cell carcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophageal junction adenocarcinoma, head and neck adenoid cystic carcinoma, head and neck carcinoma, head and neck neuroblastoma, head and neck squamous cell carcinoma, kidney chromophore carcinoma, kidney medullary carcinoma, kidney renal cell carcinoma, kidney renal papillary carcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma, kidney carcinoma, leukemia lymphocytic, leukemia lymphocytic chronic, liver cholangiocarcinoma, liver hepatocellular carcinoma, liver carcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrine carcinoma, lung non-small cell lung carcinoma, lung sarcoma, lung sarcomatoid carcinoma, lung small cell carcinoma, lung small cell undifferentiated carcinoma, lung squamous cell carcinoma, upper aerodigestive tract squamous cell carcinoma, upper aerodigestive tract carcinoma, lymph node lymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma, lymph node lymphoma mediastinal B-cell, lymph node lymphoma plasmablastic lung adenocarcinoma, lymphoma follicular lymphoma, lymphoma, non-Hodgkins, nasopharynx and paranasal sinuses undifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovary clear cell carcinoma, ovary epithelial carcinoma, ovary granulosa cell tumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductal adenocarcinoma, pancreas neuroendocrine carcinoma, peritoneum mesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma, pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma, rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexal carcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cell carcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma, small intestine gastrointestinal stromal tumors (GISTs), large intestine/colon carcinoma, large intestine adenocarcinoma, soft tissue angiosarcoma, soft tissue Ewing sarcoma, soft tissue hemangioendothelioma, soft tissue inflammatory myofibroblastic tumor, soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissue neuroblastoma, soft tissue paraganglioma, soft tissue perivascular epitheliod cell tumor, soft tissue sarcoma, soft tissue synovial sarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type, stomach adenocarcinoma intestinal type, stomach adenocarcinoma intestinal type, stomach leiomyosarcoma, thymus carcinoma, thymus thymoma lymphocytic, thyroid papillary carcinoma, unknown primary adenocarcinoma, unknown primary carcinoma, unknown primary malignant neoplasm, lymphoid neoplasm, unknown primary melanoma, unknown primary sarcomatoid carcinoma, unknown primary squamous cell carcinoma, unknown undifferentiated neuroendocrine carcinoma, unknown primary undifferentiated small cell carcinoma, uterus carcinosarcoma, uterus endometrial adenocarcinoma, uterus endometrial adenocarcinoma endometrioid, uterus endometrial adenocarcinoma papillary serous, and uterus leiomyosarcoma.

In some embodiments of any of the methods described herein, the step of determining whether a cell in a sample obtained from the subject has the at least one point mutation in a NTRK1 gene, the at least one point mutation in a NTRK2 gene, and/or the at least one point mutation in a NTRK3 gene, includes performing an assay to determine the presence of the at least one point mutation in a NTRK1 gene, the presence of the at least one point mutation in a NTRK2 gene, and/or the presence of the at least one point mutation in a NTRK3 gene, in a cell in the sample. In some embodiments of any of the methods described herein, the assay is selected from the group of: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, a single strand conformational polymorphism assay, a molecular beacon assay, a dynamic hybridization assay, a PCR-based assay, denaturing high performance liquid chromatography. In some embodiments of any of the methods described herein, the assay includes sequencing a segment of the NTRK1 gene comprising the at least one point mutation, a segment of the NTRK2 gene comprising the at least one point mutation, and/or a segment of the NTRK3 gene comprising the at least one point mutation. Some embodiments of any of the methods described herein further include confirming the diagnosis of a cancer in a subject determined to have an increased likelihood of having a cancer.

In some embodiments of any of the methods described herein, the TrkA protein includes a mutation at one or more amino acid positions selected from the group of S241F, S241H, S241Y, R314G, R314H, R314L, R314P, N318S, G319S, S320F, V321M, I510T, V511M, L512F, L512R, S552R, A553T, R554P, R554Q, R554W, A636E, A636T, A636V, G637E, G637W, M638V, R649L, R649W, R654C, R654H, N655Y, D679N, D679Y, Y680H, T687I, M688I, L689M, P690H, R692C, R692H, P695S, P696L, E697K, E747K, R748L, R748Q, R748W, P749Q, R750C, R750H, and R750L; the TrkB protein includes a mutation at one or more amino acid position(s) selected from the group of M240I, N241D, E242K, R251G, R251K, I252V, S256L, S257F, D258N, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, R598C, R598S, K599M, D600H, H602N, R603S, L664M, T665M, T665S, Q666L, Q666R, A677T, A678T, A678V, G679D, M680I, V689M, R691C, D692N, F746I, T747M, T748M, E749K, Q784H, G785V, R786Q, V787F, L788M, Q789E, G804E, C805R, and C805Y; and/or the TrkC protein includes a mutation at one or more amino acid position(s) selected from the group of V221I, R222Q, E223D, D242N, W243C, I244T, T269A, T269M, T270M, T270Q, T270V, V271L, V271M, E276D, D277E, D277G, D277N, T281I, T281P, T282M, T283A, T283K, T283M, S296I, S296R, V297I, V325M, R326C, R326G, R326H, R326L, R326P, N328S, P329N, P329S, P330Q, E344G, E344V, S345F, K346N, H349Y, V350E, E351D, Y353F, Q354K, D537E, D537Y, I538N, V539M, L540M, G545C, G545D, G550R, K551E, L560V, P562L, P562Q, P562R, P562T, K575E, D576N, P577S, P582Q, P582W, K583%, D584E, D584N, V601A, V601I, K602R, F603L, Y604F, Y604H, Y604N, C607F, G608C, G608E, G608S, D609G, D609H, D609N, D609V, G610R, P612A, P612L, P612S, P612T, D624Y, L625M, N626K, K627N, K627R, F628L, L629F, L629I, P634L, P634T, D635H, A636E, A636V, M637I, M637K, M637V, E650V, L65 IP, G652R, G652V, L653F, L653P, H677Y, R678Q, D679G, D679N, V687A, V687I, G688R, A689E, A689V, Y705N, S706I, T707M, D708N, P715L, P715S, S716Y, G717R, T730N, M731I, M731L, L732I, P738H, P738S, Y744F, R745P, R745W, K746R, K746T, G786C, G786S, R787C, R787H, R787S, P796L, P796S, D801N, Q808H, R809W, and E810K.

Also provided are kits that include one or more probes that each specifically hybridize to: a segment of a NTRK1 gene that encodes a mutation at one of amino acid positions 241, 314, 318, 319, 320, 321, 510, 511, 512, 552, 553, 554, 636, 637, 638, 649, 654, 655, 679, 680, 687, 688, 689, 690, 692, 695, 696, 697, 747, 748, 749, and 750 in a TrkA protein; a segment of a NTRK2 gene that encodes a mutation at one of amino acid positions 240, 241, 242, 251, 252, 256, 257, 258, 264, 314, 315, 401, 426, 427, 428, 440, 598, 599, 600, 602, 603, 664, 665, 666, 677, 678, 679, 680, 689, 691, 692, 746, 747, 748, 749, 784, 785, 786, 787, 788, 789, 804, and 805 in TrkB protein; or a segment of a NTRK3 gene that encodes a mutation at one of amino acid positions 221, 222, 223, 242, 243, 244, 269, 270, 271, 276, 277, 281, 282, 283, 296, 297, 325, 326, 328, 329, 344, 345, 346, 349, 350, 351, 353, 354, 537, 538, 539, 540, 545, 550, 551, 560, 562, 575, 576, 577, 582, 583, 584, 601, 602, 603, 604, 607, 608, 609, 610, 612, 624, 625, 626, 627, 628, 629, 634, 635, 636, 637, 650, 651, 652, 653, 677, 678, 679, 687, 688, 689, 705, 706, 707, 708, 715, 716, 717, 730, 731, 732, 738, 744, 745, 746, 786, 787, 796, 801, 808, 809, and 810 in a TrkC protein.

In some embodiments of any of the kits provided herein, the kit includes one or more probes that each specifically hybridize to: a segment of a NTRK1 gene that encodes a mutation selected from the group consisting of S241F, S241H, S241Y, R314G, R314H, R314L, R314P, N318S, G319S, S320F, V321M, I510T, V511M, L512F, L512R, S552R, A553T, R554P, R554Q, R554W, A636E, A636T, A636V, G637E, G637W, M638V, R649L, R649W, R654C, R654H, N655Y, D679N, D679Y, Y680H, T687I, M688I, L689M, P690H, R692C, R692H, P695S, P696L, E697K, E747K, R748L, R748Q, R748W, P749Q, R750C, R750H, and R750L in a TrkA protein; a segment of a NTRK2 gene that encodes a mutation selected from the group consisting of M240I, N241D, E242K, R251G, R251K, I252V, S256L, S257F, D258N, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, R598C, R598S, K599M, D600H, H602N, R603S, L664M, T665M, T665S, Q666L, Q666R, A677T, A678T, A678V, G679D, M680I, V689M, R691C, D692N, F746I, T747M, T748M, E749K, Q784H, G785V, R786Q, V787F, L788M, Q789E, G804E, C805R, and C805Y in TrkB protein; or a segment of a NTRK3 gene that encodes a mutation selected from the group consisting of V221I, R222Q, E223D, D242N, W243C, I244T, T269A, T269M, T270M, T270Q, T270V, V271L, V271M, E276D, D277E, D277G, D277N, T281I, T281P, T282M, T283A, T283K, T283M, S296I, S296R, V297I, V325M, R326C, R326G, R326H, R326L, R326P, N328S, P329N, P329S, P330Q, E344G, E344V, S345F, K346N, H349Y, V350E, E351D, Y353F, Q354K, D537E, D537Y, I538N, V539M, L540M, G545C, G545D, G550R, K551E, L560V, P562L, P562Q, P562R, P562T, K575E, D576N, P577S, P582Q, P582W, K583%, D584E, D584N, V601A, V601I, K602R, F603L, Y604F, Y604H, Y604N, C607F, G608C, G608E, G608S, D609G, D609H, D609N, D609V, G610R, P612A, P612L, P612S, P612T, D624Y, L625M, N626K, K627N, K627R, F628L, L629F, L629I, P634L, P634T, D635H, A636E, A636V, M637I, M637K, M637V, E650V, L651P, G652R, G652V, L653F, L653P, H677Y, R678Q, D679G, D679N, V687A, V687I, G688R, A689E, A689V, Y705N, S706I, T707M, D708N, P715L, P715S, S716Y, G717R, T730N, M731I, M731L, L732I, P738H, P738S, Y744F, R745P, R745W, K746R, K746T, G786C, G786S, R787C, R787H, R787S, P796L, P796S, D801N, Q808H, R809W, and E810K in a TrkC protein.

In some embodiments of any of the kits provided herein, the one or more probes are labeled with a detectable probe. In some embodiments of any of the kits provided herein, the one or more probes are covalently attached to a substrate. In some embodiments of any of the kits provided herein, the substrate is a film, a plate, or a bead.

As used herein, the word “a” before a noun represents one or more of the particular noun. For example, the phrase “a cell” represents “one or more cells.”

The term “subject” means a vertebrate, including any member of the class mammalia, including humans, sports or pet animals, such as horse (e.g., race horse) or dog (e.g., race dogs), and higher primates. In preferred embodiments, the subject is a human.

The term “treating” or “positive response to treatment” means an improvement in the condition of a subject having a cancer, e.g., one or more of a decrease in the size of one or more tumor(s) in a subject, a decrease or no substantial change in the growth rate of one or more tumor(s) in a subject, a decrease in metastasis in a subject, and an increase in the period of remission for a subject (e.g., as compared to the one or more metric(s) in a subject having a similar cancer receiving no treatment or a different treatment, or as compared to the one or more metric(s) in the same subject prior to treatment). Additional metrics for assessing response to a treatment in a subject having a cancer are known in the art.

The term “point mutation” means a change in the nucleotide sequence of a gene that results in a single amino acid change in a protein encoded by the gene. For example, a point mutation in a gene can result in the deletion of a single amino acid in a protein encoded by the gene or can result in the substitution of an amino acid in a wildtype version of the encoded protein with a different amino acid. Non-limiting examples of point mutations in NTRK1, NTRK2, and NTRK3 genes are described herein.

The phrase “significant level of carcinogen” is meant a level of exposure to a carcinogen that is known to increase (e.g., a statistically significant increase) the likelihood of a subject to develop a cancer (e.g., as compared to a subject that has not been exposed to the same level of exposure or has been exposed to a non-detectable amount of the carcinogen).

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram showing the position of the different point mutations detected in the NTRK3 gene (Summary) and the point mutations in NTRK3 gene that are associated with specific histologies (bottom nine rows).

FIG. 2 is a diagram showing the position of all the different point mutations detected in the NTRK3 gene with confirmed expression above background (Summary) and the point mutations in the NTRK3 gene with confirmed expression above background that are associated with specific histologies (bottom nine rows).

FIG. 3 is a graphic showing the position of a valine at amino acid position 689 or a methionine at amino acid position 689 relative to the asparagine at amino acid position 529 in TrkB protein.

DETAILED DESCRIPTION

A variety of different NTRK1, NTRK2, and NTRK3 point mutations were discovered in biopsy samples from subjects having a variety of different cancers. In view of this discovery, provided herein are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include administering to a subject identified as having a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein) a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein), methods of selecting a treatment including a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for a subject identified as having a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTKR3 described herein), methods of determining the likelihood that a subject having a cancer (e.g., any of the cancers described herein) will have a positive response to a treatment based upon whether the subject has a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTKR3 described herein), methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) in a subject having a cancer (e.g., any of the cancers described herein) based upon whether the subject has a cancer cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) based upon whether the subject has a cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein), and methods of assisting in the diagnosis of cancer (e.g., any of the cancers described herein) in a subject based upon whether the subject has a cell that has at least one point mutation in NTRK1, NTRK2, and/or NTRK3 (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein). As can be appreciated in the art, the various aspects described below can be used in any combination without limitation.

Tropomyosin Receptor Kinases (Trks)

Three different NTRK genes have been implicated for a role in cancer (e.g., through discovery of chromosome translocations resulting in constitutively active Trk fusion proteins): NTRK1, NTRK2, and NTRK3. The NTRK1, NTRK2, and NTRK3 genes encode TrkA, TrkB, and TrkC, respectively. Non-limiting exemplary amino acid and cDNA sequences for wildtype TrkA, TrkB, and TrkC are provided below. The exemplary wildtype protein and cDNA sequences provided below can be used to identify a point mutation in a NTRK1, NTRK2, or NTRK3 gene or can be used to determine mutation in a TrkA, TrkB, or TrkC protein caused by a point mutation in a NTRK1, NTRK2, or NTRK3 gene, respectively. Additional wildtype protein and cDNA sequences for TrkA, TrkB, and TrkC are known in the art.

Wildtype Human TrkA Protein Isoform A (NP_002520) (SEQ ID NO: 1)

Wildtype Human TrkA cDNA Isoform A (NM_002529) (SEQ ID NO: 2)

Wildtype Human TrkA Protein Isoform B (NP_001007793) (SEQ ID NO: 3)

Wildtype Human TrkA cDNA Isoform B (NM_001007792) (SEQ ID NO: 4)

Wildtype Human TrkB Protein (NP_006171) (SEQ ID NO: 5)

Wildtype Human TrkB cDNA (NM_006180) (SEQ ID NO: 6)

Wildtype Human TrkC Protein (NP_001012338) (SEQ ID NO: 7)

Wildtype Human TrkC cDNA (NM_001012338) (SEQ ID NO: 8)

NTRK Point Mutations

Different point mutations were discovered in NTRK1, NTRK2, and NTRK3 genes in biopsy samples from subjects having a variety of different cancers. A point mutation in a NTRK1, NTRK2, or NTRK3 gene can result, e.g., in a Trk protein (a TrkA, TrkB, and TrkC protein, respectively) that includes a substitution of an amino acid in a wildtype version of the Trk protein with a different amino acid. In other examples, a point mutation in a NTRK1, NTRK2, or NTRK3 gene can result, e.g., in a Trk protein (a TrkA, TrkB, and TrkC protein, respectively) with a deletion of an amino acid in a wildtype version of the Trk protein.

Non-limiting examples of the specific amino acid positions discovered to have mutations (e.g., substitutions or deletions) in TrkA, TrkB, or TrkC proteins in cancer cells having a NTRK1, NTRK2, or NTRK3 point mutation are listed below. Also listed below are the different specific amino acid mutations (e.g., substitutions or deletions) present in TrkA, TrkB, or TrkC proteins generated in cancer cells having a NTRK1, NTRK2, or NTRK3 point mutation, respectively.

Point mutations in NTRK1 gene were discovered to result in a TrkA protein that includes one or more (e.g., two, three, four, five, six, seven, eight, or nine) amino acid substitutions or deletions at amino acid positions: 3, 4, 5, 6, 7, 8, 10, 13, 15, 17, 18, 20, 22, 24, 25, 30, 31, 33, 34, 38, 39, 41, 42, 43, 49, 50, 52, 55, 56, 59, 62, 63, 66, 69, 71, 74, 79, 80, 85, 86, 88, 89, 90, 91, 92, 96, 97, 101, 104, 106, 107, 110, 112, 113, 115, 116, 117, 119, 126, 129, 132, 134, 138, 139, 142, 147, 149, 150, 155, 156, 157, 158, 161, 165, 166, 167, 169, 170, 171, 179, 185, 186, 189, 193, 195, 197, 198, 201, 202, 206, 208, 210, 211, 212, 214, 220, 221, 222, 223, 224, 225, 226, 228, 231, 233, 238, 239, 241, 243, 245, 246, 247, 248, 251, 252, 253, 258, 260, 261, 262, 263, 264, 266, 270, 273, 275, 277, 282, 287, 292, 293, 294, 296, 297, 298, 300, 302, 304, 306, 307, 309, 310, 311, 314, 318, 319, 320, 321, 323, 324, 326, 328, 329, 330, 335, 336, 337, 340, 341, 342, 344, 346, 347, 349, 357, 359, 360, 361, 366, 368, 371, 372, 374, 375, 379, 380, 381, 388, 389, 392, 393, 395, 397, 398, 402, 404, 406, 407, 408, 410, 411, 413, 415, 416, 417, 419, 421, 422, 425, 426, 432, 434, 440, 444, 447, 452, 453, 454, 455, 457, 460, 461, 465, 468, 471, 472, 475, 476, 477, 478, 479, 480, 484, 485, 486, 487, 488, 489, 494, 495, 500, 502, 503, 507, 508, 510, 511, 512, 515, 517, 518, 520, 522, 526, 527, 530, 533, 537, 539, 540, 541, 543, 547, 549, 550, 551, 552, 553, 554, 556, 559, 561, 566, 570, 573, 574, 575, 577, 578, 580, 583, 585, 587, 591, 593, 594, 595, 599, 602, 603, 606, 607, 609, 612, 614, 615, 616, 618, 620, 623, 626, 630, 631, 636, 637, 638, 639, 640, 641, 642, 644, 647, 649, 651, 654, 655, 657, 660, 661, 663, 664, 666, 671, 674, 677, 679, 680, 682, 683, 684, 686, 687, 688, 689, 690, 692, 695, 696, 697, 699, 702, 705, 706, 709, 710, 712, 715, 719, 723, 725, 728, 733, 734, 736, 741, 743, 744, 747, 748, 749, 750, 751, 753, 754, 755, 760, 761, 762, 763, 766, 768, 771, 772, 776, 777, 779, 780, 788, 790, and 791 (e.g., amino acid positions corresponding to those in wildtype sequence NP_002520 (SEQ ID NO: 1) or NP_001007793 (SEQ ID NO: 3)). Different specific amino acid substitutions or deletions present in TrkA protein generated in a cancer cell include one or more (e.g., two, three, four, five, six, seven, eight, or nine) of following: R3P, R3Q, G4A, AST, ASV, R6W, R7S, G8E, A10E, A10T, V13I, W15C, A17T, T18M, G20D, W22R, L22Q, A24S, W25C, S30P, R31I, A33S, A33V, A34T, L38W, D38N, A39S, C41W, P42T, H43Q, R49G, R49P, R49Q, C50Y, R52L, R52Q, A55D, L56M, L59F, L62P, P63S, E66D, T69I, L71I, E74K, L79Q, Q80R, R85C, D86N, D86Y, R88K, R88S, G89S, L90M, L90del, G91R, E92K, L96V, T97I, S101C, S101N, S101R, R104H, V106M, A107V, A110V, H112Y, F113L, P115S, R116L, R116Q, R116W, L117P, R119C, R119H, R119P, A126D, A126P, A126T, S129F, W132F, W132R, T134N, L138H, S139F, E142K, G147E, P149A, P149H, L150P, A155V, L156Q, R157C, R157L, R157P, W158R, R161C, R161P, E165D, E165del, G166R, L167M, G169E, G169R, V170L, P171S, P171T, G179R H185N, M186T, A189V, V193L, T195M, K197R, V198F, P201H, P201del, N202S, D206N, G208E, G208R, D210N, V211E, V211L, L212V, R214Q, R214W, R220W, G221D, G221V, L222Q, E223Q, Q224H, A225S, G226D, G226S, I228V, E231K, E233K, E233Q, V238M, M239I, S241F, S241H, S241Y, G243D, P245S, S246F, L247V, G248E, G248R, L251M, A252S, N253D, L258I, L258V, R260G, R260M, K261E, K261N, N262K, V263M, T264K, T264M, W266S, D270G, D270N, R273Q, R273W, E275A, S277F, V282I, S287I, T292M, A293V, V294A, M296K, H297Q, H298Q, C300R, C300Y, P302L, S304Y, D306E, G307A, P309S, A310E, A310S, P311L, R314G, R314H, R314L, R314P, N318S, G319S, S320F, V321M, N323S, E324D, E324K, S326R, I328V, F329V, T330A, P335L, A336E, A337P, A337T, T340I, V341M, R342Q, R342W, G344E, G344W, L346P, R347C, R347G, R347H, N349K, N349S, G357S, Y359C, T360M, L361R, P366L, P366R, P366S, P366T, G368C, S371F, A372S, A372T, I374N, M375I, M375V, M379T, D380G, N381S, E388D, E388K, D389Y, P392S, V393F, F395L, P397L, V398L, S402I, S402R, S404P, D406Y, P407L, P407R, V408G, K410N, K411N, K411del, E413K, E413Q, P415S, F416S, G417V, S419L, A421T, V422L, A425S, V426I, L432R, T434M, N440K, N440S, R444P, R444Q, R444W, K447M, K447N, K447T, R452C, R452G, P453L, P453Q, P453T, A454T, V455M, A457V, D460N, G461R, S465F, S465del, F468L, L471F, G472S, S475C, S475F, S475T, L476M, S477Y, S477_insS, P478L, T479I, E480K, E480Q, S484Y, G485R, L486I, Q487L, G488C, G488S, H489Q, H489Y, P494T, Q495R, A500T, V502A, H503N, H503Y, R507C, R507H, R508Q, R508W, I510T, V511M, L512F, L512R, E515K, G517R, E518K, A520T, G522W, L526F, L526P, A527T, H530Y, L533Q, D537E, D537N, M539L, M539R, L540Q, V541M, V543A, K547T, A549T, A549V, S550Y, E551D, E551V, S552R, A553T, R554P, R554Q, R554W, D556N, R559H, A561T, M566K, Q570R, V573M, R574C, R574H, F575L, G577S, V578I, T580I, R583C, R583L, L585R, M587T, Y591C, R593W, H594Q, G595R, R599H, R602Q, S603P, P606H, D607N, K609N, A612S, A612V, G614A, G614V, E615K, E615Q, D616H, D616N, A618V, G620C, G623C, Q626K, V630A, A631D, A636E, A636T, A636V, G637E, G637W, M638V, V639L, V639M, Y640C, L641M, A642S, A642V, L644M, V647C V647L, R649L, R649W, L651M, R654C, R654H, N655Y, L657P, L657V, Q660L, G661E, V663E, V664I, I666T, M671T, D674E, D674N, S677N, D679N, D679Y, Y680H, R682C, R682H, R682S, V683G, G684E, R686C R686H, T687I, M688I, L689M, P690H, R692C, R692H, P695S, P696L, E697K, I699V, R702C, R702H, R702L, R702S, T705S, T706K, D709N, D709Y, V710M, S712R, V715M, E719D, E719K, Y723C, K725M, K725T, W728R, N733S, T734M, A736E, A736T, T741M, G743R, R744C, R744H, E747K, R748L, R748Q, R748W, P749Q, R750C, R750H, R750L, A751D, P753Q, P754T, E755Q, M760I, M760V, R761Q, R761W, G762R, C763F, R766L, R766W, P768S, R771H, H772R, D776E, D776N, V777A, A779T, R780G, R780W, P788L, P788S, V790I, V790L, and Y791H (e.g., as compared to the wildtype sequence NP_002520 (SEQ ID NO: 1) or NP_001007793 (SEQ ID NO: 3), e.g., as shown in Tables 1 and 2).

Point mutations in NTRK2 gene were discovered to result in a TrkB protein that includes one or more amino acid substitutions or deletions at amino acid positions: 7, 9, 10, 14, 23, 26, 28, 29, 31, 34, 35, 37, 42, 45, 46, 47, 51, 53, 56, 57, 60, 65, 66, 69, 70, 72, 74, 75, 78, 80, 81, 82, 84, 88, 89, 97, 98, 100, 101, 105, 110, 113, 120, 122, 124, 125, 132, 133, 136, 138, 139, 146, 147, 158, 159, 166, 169, 172, 173, 175, 185, 187, 187, 191, 193, 195, 196, 198, 199, 202, 203, 207, 209, 209, 210, 221, 222, 223, 224, 225, 228, 230, 234, 240, 241, 242, 249, 251, 252, 254, 256, 257, 258, 261, 264, 266, 268, 272, 279, 280, 286, 289, 292, 293, 293, 294, 295, 296, 304, 310, 311, 314, 315, 319.321, 326, 328, 331, 335, 341, 343, 349, 350, 354, 357, 358, 370, 373, 377, 379, 385, 386, 387, 388, 389, 390, 394, 395, 398, 401, 408, 410, 414, 416, 419, 423, 423, 426, 427, 428, 430, 432, 435, 440, 442, 446, 449, 452, 454, 455, 458, 460, 464, 475, 476, 480, 481, 482, 483, 484, 486, 496, 498, 501, 503, 514, 515, 517, 519, 521, 524, 528, 530, 539, 545, 547, 549, 552, 553, 558, 559, 561, 562, 563, 564, 566, 569, 574, 577, 578, 579, 580, 581, 582, 584, 589, 592, 595, 598, 599, 600, 602, 603, 608, 615, 615, 616, 618, 622, 624, 624, 625, 627, 629, 630, 632, 634, 638, 639, 646, 648, 649, 652, 653, 654, 656, 657, 658, 660, 662, 664, 665, 666, 668, 670, 671, 673, 674, 677, 678, 679, 680, 682, 684, 685, 689, 691, 692, 698, 698, 699, 700, 702, 706, 709, 710, 714, 715, 716, 725, 726, 727, 729, 736, 737, 741, 742, 744, 746, 747, 748, 749, 750, 752, 754, 755, 756, 758, 760, 761, 762, 766, 769, 773, 777, 779, 782, 783, 784, 785, 786, 787, 788, 789, 792, 793, 795, 797, 799, 802, 804, 805, 810, 812, 818, 821, 822, 825, 829, and 831 (e.g., amino acid positions corresponding to those in wildtype sequence NP_006171 (SEQ ID NO: 5)). Different specific amino acid substitutions or deletions present in TrkB protein generated in a cancer cell include one or more of following: W7R, G9E, G9V, P10H, R14W, V23A, V23M, W26R, A28D, A29T, A31T, T34A, T34R, S35F, K37R, R42Q, C45F, C45R, C45Y, S46R, D47N, G51D, V53A, P56L, P56S, R57S, P60H, P65H, P65T, E66D, T69P, T69S, E70K, F72L, A74S, N75K, R78K, E80Q, I81F, 182V, E84K, E88K, E88Q, A89T, T97A, I98V, D100N, S101F, F105L, A110E, K113R, I120N, I120V, F122I, R124Q, N125K, R132S, K133N, R136C, R136H, L138F, D139H, V146A, V146L, G147S, W158C, I159F, I159M, K166T, P169S, Q172K, D173Y, Y175H, P185L, A187E, A187S, I191T, N193S, G195A, L196F, S198T, A199T, A202D, A203S, T207I, E209D, E209K, E210V, A221V, G222D, D223H, P224S, V225I, M228T, W230L, N234Y, M240I, N241D, E242K, S249F, S249Y, R251G, R251K, I252V, N254S, S256L, S257F, D258N, G261R, I264M, C266S, C266Y, A268V, V272E, V279A, N280I, A286P, A286T, I289V, L292I, E293D, E293K, S294F, P295S, T296I, P304L, N310A (deletion), P311H, A314E, A314G, A314V, L315F, Y319C, G321V, E326D, K328Q, C331F, C331Y, H335L, E341K, E341V, H343D, D349Y, N350I, N350K, M354I, G357R, D358Y, D370Y, Q373L, H377Y, M379T, M379V, D385G, D386N, G387C, A388V, N389I, P390R, D394H, D394N, D394Y, V395A, E398K, G401A, G401E, G401R, G408R, T410N, S414I, E416G, S419F, T423I, T423S, T426I, G427S, R428Q, H430Y, S432L, A435V, A440S, A440T, A440V, V442L, V442M, C446Y, V449I, F452L, L454I, K455N, R458G, S460F, S460T, S460Y, M464V, V475A, K476E, K476I, G480D, V481I, G482R, G482V, P483T, A484T, V486F, V486I, P496R, P496S, H498N, H498Y, S501C, G503W, P514L, P514S, D515N, V5171, 1519A, M521L, I524F, E528K, P530L, Q539H, F545V, Q547R, I549M, H552Q, N553S, R558K, E559D, E559K, G561S, E562K, G563R, G563V, A564T, G566E, F569L, Y574H, C577S, P578H, P578L, P578S, P578T, E579D, Q580P, D581N, K582T, L584F, T589S, D592A, D595E, R598C, R598S, K599M, D600H, H602N, R603S, L608M, H615L, H615Y, I616T, K618R, V622I, V624L, V624M, E625K, D627N, L629I, I630V, V632I, E634Q, H638L, G639R, G639V, R646M, H648Q, G649S, A652V, V653M, L654V, A656D, E657K, E657Q, G658D, P660L, P660T, T662M, L664M, T665M, T665S, Q666L, Q666R, Q668L, L670M, H671R, A673G, Q674H, A677T, A678T, A678V, G679D, M680I, Y682C, A684E, A684T, A684V, S685Y, V689M, R691C, D692N, C698R, C698W, L699P, V700F, E702D, V706M, G709R, D710Y, S714A, R715Q, R715W, D716N, V725G, G726C, G727D, T729S, M736I, P737T, I741N, I741V, M742L, R744K, F746I, T747M, T748M, E749K, S750N, V752I, S754T, L755M, G756W, V758E, V758L, V758M, W760R, E761D, E761Q, I762M, G766D, G766S, P769T, L773M, E777Q, I779M, I782M, T783I, Q784H, G785V, R786Q, V787F, L788M, Q789E, R792C, T793A, T793M, P795T, E797K, Y799N, M802L, G804E, C805R, C805Y, P810T, M812I, G818D, T821N, T821S, L822F, N825D, A829S, and P831L (e.g., compared to the wildtype sequence NP_006171 (SEQ ID NO: 5)).

Point mutations in NTRK3 gene were discovered to result in a TrkC protein that includes one or more amino acid substitutions or deletions at amino acid positions: 4, 5, 7, 8, 9, 14, 19, 21, 25, 27, 35, 36, 37, 39, 45, 46, 48, 49, 55, 63, 64, 67, 69, 71, 75, 76, 78, 82, 83, 85, 89, 90, 95, 96, 98, 99, 101, 111, 113, 114, 115, 116, 117.119, 120, 121, 123, 124, 125, 126, 127, 130, 133, 134, 138, 140, 147, 148, 149, 152, 153, 154, 156, 157, 158, 159, 161, 163, 164, 165, 169, 171, 172, 174, 176, 178, 179, 184, 188, 189, 192, 194, 195, 196, 199, 200, 201, 202, 205, 208, 209, 210, 212, 215, 217, 218, 221, 222, 223, 227, 230, 232, 235, 239, 240, 242, 243, 244, 248, 249, 252, 253, 254, 255, 256, 260, 262, 266, 269, 270, 271, 273, 276, 277, 279, 281, 282, 283, 287, 289, 290, 292, 293, 294, 296, 297, 299, 301, 304, 305, 306, 308, 309, 312, 313, 314, 316, 320, 322, 323, 325, 326, 328, 329, 330, 332, 334, 336, 337, 339, 340, 343, 344, 345, 346, 349, 350, 351, 353, 354, 356, 357, 359, 361, 362, 364, 370, 372, 376, 378, 379, 380, 382, 384, 388, 389, 392, 393, 394, 396, 397, 398, 399, 401, 404, 405, 408, 411, 412, 415, 416, 417, 418, 421, 423, 425, 426, 429, 430, 431, 433, 435, 436, 437, 439, 448, 449, 450, 451, 452, 455, 457, 458, 459, 460, 461, 463, 464, 466, 467, 468, 469, 473, 474, 477, 478, 487, 488, 490, 491, 492, 494, 496, 497, 499, 501, 506, 507, 508, 509, 511, 512, 513, 514, 516, 518, 519, 520, 521, 522, 526, 527, 529, 531, 533, 534, 535, 536, 537, 538, 539, 540, 542, 543, 545, 547, 550, 551, 560, 562, 565, 566, 567, 568, 569, 572, 575, 576, 577, 579, 581, 582, 583, 584, 586, 588, 590, 592, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 607, G608, 609, 610, 612, 615, 621, 623, 624, 625, 626, 627, 628, 629, 631, 632, 634, 635, 636, 637, 643, 644, 645, 647, 648, 649, 650, 651, 652, 653, 655, 656, 658, 660, 661, 663, 664, 665, 667, 668, 669, 672, 675, 677, 678, 679, 683, 685, 687, 688, 689, 693, 694, 695, 696, 697, 699, 700, 701, 702, 704, 705, 706, 707, 708, 710, 712, 714, 715, 716, 717, 719, 720, 723, 724, 726, 730, 731, 732, 735, 736, 738, 741, 744, 745, 746, 749, 751, 752, 753, 754, 755, 757, 759, 760, 762, 764, 766, 768, 772, 773, 777, 778, 781, 782, 783, 784, 786, 787, 789, 790, 791, 791, 792, 793, 796, 801, 805, 806, 807, 808, 809, 810, 812, 813, 814, 815, 819, 822, 824, 825, 826, 827, 828, 830, 832, 833, 834, and 836 (e.g., amino acid positions corresponding to those in wildtype sequence NP_001012338 (SEQ ID NO: 7)). Different specific amino acid substitutions or deletions present in TrkC protein generated in a cancer cell include one or more of following: S4C, S4F, L5I, P7L, P7R, A8D, K9E, K9N, R14P, G19E, V21F, V21I, Y25C, G27A, N35S, C36W, V37A, S39R, C45W, R46P, R46W, P48L, D49G, P55S, G63W, N64K, G67E, A69T, I71V, D75G, D75N, I76T, R78K, R78S, S82F, I83V, 185M, R89C, R89H, R89S, S90N, N95S, A96S, A96T, D98G, D98N, M99I, L101I, K111N, S113T, G114E, L115F, L115P, L115R, R116Q, R116W, S117N, Q119H, Q119K, P120H, R121G, R121K, F123L, A124V, K125E, K125N, N126K, P127H, R130C, R130H, N133H, L134Q, R138Q, R138W, T140N, F147L, Q148H, T149M, T149R, L152I, R153Q, E154K, Q156H, Q56R, L157M, E158K, Q159H, Q159K, F161I, N163T, C164G, C164S, S165N, R169S, M171L, Q172H, W174L, E176K, G178E, G178V, E179K, S184C, S184N, S184R, Y188C, Y188F, Y188H, C189F, A192T, G194D, S195C, S195F, Q196K, L199H, L199P, L99V, F200V, R201C, M202I, S205G, D208E, D208N, L209I, L209P, L209R, L209V, P210S, I212M, S215T, V217A, V217I, N218S, V221I, R222Q, E223D, A227T, T230S, N232S, G235E, G235R, P239H, P239S, P239T, D240G, D240H, D242N, W243C, I244T, L248M, Q249H, N252S, N252T, T253N, H254Q, Q255H, T256N, W260R, N262S, I266V, T269A, T269M, L270M, L270Q, L270V, V271L, V271M, V273M, V273A, E276D, D277E, D277G, D277N, G279D, T281I, T281P, L282M, T283A, T283K, T283M, E287D, E287Q, V289A, V290A, M292I, M292V, S293R, N294T, S296I, S296R, V297I, L299A, V301F, P304L, P304S, P304T, P305Q, P305R, P305S, P305T, R306C, R306H, R306P, V308L, S309I, E312K, E312Q, P313T, E314A, E314D, E314Q, R316C, R316H, C320F, E322A, E322K, E322Q, F323L, V325M, R326C, R326G, R326H, R326L, R326P, N328S, P329N, P329S, P330Q, T332M, H334Q, L336R, H337R, G339K, Q340H, Q340K, R343L, E344G, E344V, S345F, K346N, H349Y, V350E, E351D, Y353F, Q354K, G356E, G356R, G356Y, E357D, S359F, G361N, G361S, C362F, L364F, H370N, N372K, Y376N, L378V, I379V, A380P, A380V, N382H, N382I, N382T, L384M, N388K, Q389E, Q389H, N392S, G393D, G393S, H394Q, L396I, K397N, E398D, E398K, P399L, P401Q, P401S, T404M, T404S, D405N, D405V, I408M, D411E, D411N, E412K, P415H, P415S, T416I, P417L, P418H V421L, H423Q, P425S, E426K, T429I, F430V, G431V, G431W, S433F, A435E, V436A, V436F, G437E, A439P, V448A, L449P, F450L, V451I, M452I, M452K, M452L, M452V, K455N, K455R, G457C, G457V, R458P, R459G R459W, S460T, K461R, G463R, G463V, M464I, G466C, P467H, P467S, V468L, V468M, A469D, G473C, E474G, S477L, A478G, G487C, G487S, I488T, T490K, T490M, P491H, S492L, L494M, A496E, A4% V, G497R, G497V, G497W, D499N, V501L, T506A, T506S, R507C, R507H, R507P, I508T, P509L, P509S, I511T, E512K, N513I, N513K, P514H, P514S, Y516F, R518C, R518H, Q519E, Q519L, G520E, H521N, N522K, P526A, P526Q, D527E, Y529N, Q531R, I533F, I533L, K534E, K534R, R535M, R536I, R536T, D537E, D537Y, I538N, V539M, L540M, R542L, R542Δ, E543D, G545C, G545D, G547E, G547V, G550R, K551E, L560V, P562Δ, P562L, P562Q, P562R, P562T, D565H, K566N, M567T, L568F, V569L, K572N, K575E, D576N, P577S, L579M, A581D, R582Q, R582W, K583T, D584E, D584N, Q586K, Q586L, E588Q, E590D, E590K, L592I, L595P, Q596K, H597N, H597Q, E598G, H599L, H599Y, I600V, V601A, V601I, K602R, F603L, Y604F, Y604H, Y604N, G605V, C607F, G608C, G608E, G608S, D609C D609H, D609N, D609V, G610R, P612A, P612L, P612S, P612T, M615I, K621N, G623E, D624Y, L625M, N626K, K627N, K627R, F628L, L629F, L629I, A631V, H632N, H632Y, P634L, P634T, D635H, A636E, A636V, M637I, M637K, M637V, Q643E, Q643H, P644T, R645C, R645L, R645S, A647D, A647I, K648N, G649S, G649V, E650V, L651P, G652R, G652V, L653F, L653P, Q655K, Q655A, M656R, H658N, H658Y, A660T, S661G, I663V, A664P, A664S, S665L, M667I, M667L, V668M, Y669C, Y669S, S672Y, F675S, H677Y, R678Q, D679G, D679N, R683S, C685F, V687A, V687I, G688R, A689E, A689V, V693L, K694N, I695F, I695T, G696R, G696W, D697N, G699S, M700T, S701F, R702I, V704F, Y705N, S706I, T707M, D708N, Y710C, Y710H, L712F, L712P, N714S, P715L, P715S, S716Y, G717R, D719N, F720I, F720L, W723R, C724F, V726L, T730N, M731I, M731L, L732I, R735C, R735H, R735S, W736C, P738H, P738S, S741C, S741I, Y744F, R745P, R745W, K746R, K746T, T749K, S751N, D752N, V753L, W754C, W754L, S755R, G757E, G757R, G757W, I759M, L760F, E762D, E762K, F764I, Y766F, K768E, K768R, F772L, Q773K, T777M, E778K, E778V, E781K, C782R, C782S, I783N, T784S, G786C, G786S, R787C, R787H, R787S, L789F, E790V, R791Q, R791W, P792H, R793L, R793Q, P796L, P796S, D801N, G805R, G805W, C806S, W807G, Q808H, R809W, E810K, Q812H, Q813E, Q813K, R814Q, L815M, E819K, K822R, L824F, H825R, H825Y, A826G, A826S, A826V, L827F, G828E, G828W, A830D, P832A, P832R, P832T, I833V, Y834C, Y834N, D836E, and D836N (e.g., compared to the wildtype sequence NP_001012338). In some biopsy samples, mutation in the NTRK3 gene results in a TrkC protein lacking amino acids 548 to 562 in the wildtype TrkC protein (e.g., as compared to NP_001012338 (SEQ ID NO: 7)).

As one skilled in the art can appreciate, the specific substitutions listed above are exemplary. For example, when a naturally-occurring amino acid at an amino acid position is substituted with a different amino acid, it is understood that an amino acid having a chemically-related amino acid side chain may also be substituted (and detected in a cancer cell). Amino acids that have chemically-related amino acid side chains are listed in Table A.

TABLE A

Chemically Related Amino Acid Side Chains

Positively-Charged
Lysine, Arginine, Histidine

Side Chains

Negatively-Charged
Glutamate and Aspartate

Side Chains

Nonpolar and/or
Glycine, Alanine, Valine, Leucine,

Aliphatic Side Groups
Isoleucine, and Proline

Polar, Uncharged Side
Serine, Threonine, Cysteine, Methionine,

Groups
Asparagine, Glutamine

Aromatic Side Chains
Phenylalanine, Tyrosine, and Tryptophan

Any of the point mutations described herein may result in, e.g., increased the catalytic activity of a TrkA, TrkB, or TrkC kinase. Any of the point mutations described herein may result in, e.g., a decrease in the auto-inhibited conformation of a Trk kinase (e.g., a TrkA, TrkB, or TrkC kinase). Any of the point mutations described herein may result in, e.g., an increase in the activated conformation of a Trk kinase (e.g., a TrkA, TrkB, or TrkC kinase).

Isolating Genomic DNA from a Biopsy Sample

Methods of isolating genomic DNA from biopsy sample are well known in the art. For example, a number of commercially available kits can be used to isolate genomic DNA from a sample containing mammalian cells (e.g., a biopsy sample). Non-limiting examples of commercially available kits for the isolation of genomic DNA from a sample containing mammalian cells include: ChargeSwitch® gDNA Tissue Kit (Life Technologies), Genomic DNA Isolation Kit (Norgen Biotek Corp., Ontario, Canada). QIAmp DNA FFPE (Qiagen), QIAsymphony DSP DNA kits (Qiagen), REPLI-g Mini Kit (Qiagen). Generation Capture Plate Kit (Qiagen), QI Amp 96 DNA Blood Kit (Qiagen), QIAmp DNA Mini kit (Qiagen), Biosprint 15 DNA Bloot Kit (Qiagen), Biosprint 96 DNA Blood Kit (Qiagen), MagAttract DNA Mini M48 Kit (Qiagen), QIAmp DNA Blood BioRobot 9604 Kit (Qiagen), QiAmp DNA Investigator Kit (Qiagen), QIAmp DNA Micro Kit, Xtreme DNA Isolation Kit (Isohelix; Harrietsham, Kent, UK), DDK DNA Isolation Kit (Isohelix), and XtraClean DNA kit (Isohelix). Genomic DNA can be isolated from a sample (e.g., a biopsy sample) using these and other commercially available genomic DNA isolation kits by following the manufacturer's instructions.

An exemplary method for isolating genomic DNA from a sample (e.g., a biopsy sample) include the steps of: lysing mammalian cells present in the sample, precipitating proteins in the lysate, removing the supernatant, precipitating genomic DNA out of the supernatant, washing the genomic DNA pellet with ethanol, and rehydrating the genomic DNA pellet in a pharmaceutically acceptable buffer (e.g., sterile or filtered water, or a buffered solution).

Assays for Determining the Presence of a Point Mutation

Some of the methods provided herein include a step of performing an assay to determine the presence of at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTKR3 described herein) in a cell (e.g., cancer cell) in a sample from the subject (e.g., a biopsy sample).

A variety of assays for determining the presence of one or more point mutations in a cell (e.g., a cancer cell) are known in the art. Non-limiting examples of such assays (which can be used in any of the methods described herein) include: denaturing gradient gel electrophoresis (DGGE) (Nollau et al., Clin. Chem. 43:1114-1128, 1997), temperature gradient gel electrophoresis (TGGE) (Nollau et al., Clin. Chem. 43:1114-1128, 1997), temperature gradient capillary electrophoresis, single strand conformational polymorphism assays (see, e.g., Tahira et al., Human Mutat. 26:69-77, 2005), molecular beacon assays (see, e.g., Totowa, N.J., Vol. 212, pp. 111-128, 2003), dynamic hybridization (see, e.g., Howell et al., Nature Biotechnol. 17:87-88, 1999), PCR-based assays (e.g., tetraprimer ARMS-PCR (see, e.g., Zhang et al., Plos One 8:e62126, 2013), real-time PCR, allele-specific PCR (see, e.g., Gaudet et al., Methods Mol. Biol. 578:415-424, 2009), and TaqMan Assay Genotyping (see, e.g., Woodward, Methods Mol. Biol. 1145:67-74, 2014, and TaqMan® OpenArray® Genotyping Plates from Life Technologies)), Flap endonuclease assays (also called Invader assays) (see, e.g., Olivier et al., Mutat. Res. 573:103-110, 2005), oligonucleotide ligation assays (see, e.g., Bruse et al., Biotechniques 45:559-571, 2008), or, denaturing high performance liquid chromatography (see, e.g., Yu et al., J. Clin. Pathol. 58:479-485, 2005), high-resolution melting of an amplified sequence containing the point mutation (see, e.g., Wittwer et al., Clinical Chemistry 49:853-860, 2003), or sequencing (e.g., Maxam-Gilbert sequencing, chain-termination methods, shotgun sequencing, bridge PCR, and next-generation sequencing methods (e.g., massively parallel signature sequencing, polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing, SOLiD sequencing, Ion Torrent semiconductor sequence, DNA nanoball sequencing, heliscope single molecule sequencing, and single molecule real-time sequencing)). Additional details and a summary of various next-generation sequencing methods are described in Koboldt et al., Cell 155:27-38, 2013.

In some embodiments, the assay used to determine the presence of the at least one point mutation in NTRK1, NTRK2, and/or NTRK3 includes a PCR assay (e.g., a real-time PCR-assay, e.g., a real-time PCR-based genotyping assay) (with or without a prior pre-amplification step). In some embodiments of any of the methods described herein the assay used to determine the presence of at least one point mutation in NTRK1, NTRK2, and/or NTRK3 is performed using TaqMan®-based sequencing (e.g., TaqMan®-based OpenArray® sequencing, e.g., high throughput TaqMan®-based Open Array® sequencing) (with or without a prior pre-amplification step). Methods for designing primers for use in the assays described herein are well-known in the art. For example, several vendors provide free software for designing forward and reverse primers for use in any of the assays described herein. A forward or reverse primer for use in any of the assays described herein can contain at least 10 (e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some examples, a forward or reverse primer used in any of the assays described herein can include a label (e.g., any of the exemplary labels described herein) or can include a contiguous tag sequence (e.g., between about 5 nucleotides and about 25 nucleotides, between about 10 nucleotides and about 25 nucleotides, between about 10 nucleotides and 20 nucleotides, between about 5 nucleotides and about 20 nucleotides) that does not hybridize to a sequence within the subject's genome (e.g., the human genome).

In some embodiments, the assay includes the use of one or more probes (e.g., detectably labeled probes) that specifically hybridize to one or more segments of a NTRK1, NTRK2, and/or NTRK3 gene that include a point mutation (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRk3 described herein). For example, the one or more probes can have 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. Additional description of the probes that can be used in exemplary assays are described herein.

Subjects

In various embodiments of the methods described herein, the subject can be previously identified or diagnosed as having a cancer (e.g., any of the cancers described herein). A subject can, e.g., be previously identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, or ten) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein). For example, a subject can be previously identified as having at least one (e.g., two, three, four, five, six, seven, eight, nine, or ten) point mutation in a NTRK2 gene that results in the expression of a TrkB protein including a mutation at one or more (e.g., two, three, four, or five) amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., a TrkB protein including one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) of M240I, N241D, E242K, I264M, A314E, A314C A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M).

In the methods of predicting a subject's risk of developing a cancer and the methods of assisting in the diagnosis of a cancer, the subject can be an undiagnosed subject, the subject can be identified as having been exposed to a significant level of carcinogen(s), the subject can be suspected of having a cancer (e.g., any of the cancers described herein), the subject can present with one or more (e.g., two, three, four, or five) symptoms of cancer (e.g., any of the symptoms of cancer described herein), and/or the subject is known to an elevated risk of developing a cancer (e.g., a family history of cancer).

Cancer

Methods of treating a cancer are provided herein. Point mutations in NTRK1, NTRK2, and/or NTRK3 were detected in biopsy samples obtained from subjects having a variety of different cancers including, but not limited to: adenocarcinoma, adrenal gland cortical carcinoma, adrenal gland neuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bile duct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acute myelocytic, bone marrow lymph proliferative disease, bone marrow multiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma, brain medulloblastoma, brain meningioma, brain oligodendroglioma, breast adenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma in situ, breast invasive ductal carcinoma, breast invasive lobular carcinoma, breast metaplastic carcinoma, cervix neuroendocrine carcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, esophagus and stomach carcinoma, eye intraocular melanoma, eye intraocular squamous cell carcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophageal junction adenocarcinoma, head and neck adenoid cystic carcinoma, head and neck carcinoma, head and neck neuroblastoma, head and neck squamous cell carcinoma, kidney chromophore carcinoma, kidney medullary carcinoma, kidney renal cell carcinoma, kidney renal papillary carcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma, kidney carcinoma, leukemia lymphocytic, leukemia lymphocytic chronic, liver cholangiocarcinoma, liver hepatocellular carcinoma, liver carcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrine carcinoma, lung non-small cell lung carcinoma, lung sarcoma, lung sarcomatoid carcinoma, lung small cell carcinoma, lung small cell undifferentiated carcinoma, lung squamous cell carcinoma, upper aerodigestive tract squamous cell carcinoma, upper aerodigestive tract carcinoma, lymph node lymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma, lymph node lymphoma mediastinal B-cell, lymph node lymphoma plasmablastic lung adenocarcinoma, lymphoma follicular lymphoma, lymphoma, non-Hodgkins, nasopharynx and paranasal sinuses undifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovary clear cell carcinoma, ovary epithelial carcinoma, ovary granulosa cell tumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductal adenocarcinoma, pancreas neuroendocrine carcinoma, peritoneum mesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma, pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma, rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexal carcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cell carcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma, small intestine gastrointestinal stromal tumors (GISTs), large intestine/colon carcinoma, large intestine adenocarcinoma, soft tissue angiosarcoma, soft tissue Ewing sarcoma, soft tissue hemangioendothelioma, soft tissue inflammatory myofibroblastic tumor, soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissue neuroblastoma, soft tissue paraganglioma, soft tissue perivascular epitheliod cell tumor, soft tissue sarcoma, soft tissue synovial sarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type, stomach adenocarcinoma intestinal type, stomach adenocarcinoma intestinal type, stomach leiomyosarcoma, thymus carcinoma, thymus thymoma lymphocytic, thyroid papillary carcinoma, unknown primary adenocarcinoma, unknown primary carcinoma, unknown primary malignant neoplasm, lymphoid neoplasm, unknown primary melanoma, unknown primary sarcomatoid carcinoma, unknown primary squamous cell carcinoma, unknown undifferentiated neuroendocrine carcinoma, unknown primary undifferentiated small cell carcinoma, uterus carcinosarcoma, uterus endometrial adenocarcinoma, uterus endometrial adenocarcinoma endometrioid, uterus endometrial adenocarcinoma papillary serous, and uterus leiomyosarcoma. See, e.g., Tables 1-4.

Additional examples of cancers include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, B-cell cancer, bile duct cancer, bladder cancer, bone cancer (e.g., osteosarcoma, malignant fibrous histiocytoma, and Ewing sarcoma), brain cancer (e.g., astrocytoma, brain and spinal cord tumor, brain stem glioma, central nervous system atypical teratoid/rhabdoid tumor, central nervous system embryonal tumors, central nervous system germ cell tumors, craniopharyngioma, and ependymoma), breast cancer, bronchogenic carcinoma, bronchus cancer, cancer of hematological tissues, cancer of the oral cavity or pharynx, carcinoid tumor, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer (e.g., intraocular melanoma and retinoblastoma), fallopian tube cancer, fibrosarcoma, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioblastoma (e.g., glioblastoma multiforme), glioma (e.g., lower-grade glioma), hairy cell leukemia, head and neck cancer, heart cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, inflammatory myofibroblastic tumors, intrahepatic cholangiocarcinoma, intraocular melanoma, islet cell tumor, kidney cancer (e.g., renal cell cancer or Wilms tumor), kidney carcinoma, Langerhans cell histiocytosis, large cell neuroendocrine cancer, laryngeal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia), lip and oral cavity cancer, liver cancer, liver carcinoma, lung cancer (e.g., lung adenocarcinoma), lymphoma (e.g., Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and primary central nervous system lymphoma), malignant fibrous histiocytoma of bone and osteosarcoma, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, mouth cancer, mouth carcinoma, multiple myeloma, myelodysplastic syndromes, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neoplasm (e.g., a melanocystic neoplasm or lymphoid neoplasm), nephroma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary thyroid carcinoma, paraganglioma, parathyroid cancer, pediatric glioma, penile cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pituitary tumor, plasma cell neoplasm, primary peritoneal cancer, prostate cancer, rectum carcinoma, renal cell cancer, retinoblastoma, salivary gland cancer, sarcoma (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, and undifferentiated sarcoma), secretory breast carcinoma. Sezary syndrome, skin cancer (e.g., melanoma and Merkel cell carcinoma), small bowel cancer, small cell lung cancer, small intestine cancer, large intestine/colon carcinoma, large intestine adenocarcinoma, soft tissue sarcoma, Spitz nevi. Spitz tumors, spitzoid melanoma, stomach cancer, squamous cell carcinoma, squamous neck cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid carcinoma, urethral cancer, uterine cancer, uterine corpus endometrioid carcinoma, urinary bladder cancer, urinary tract carcinoma, vaginal cancer, vulvar cancer, and Wilms tumor.

Methods of diagnosing a cancer (e.g., any of the cancers described herein) are known in the art. For example, a health care professional (e.g., a physician) can diagnose a subject as having a cancer by observing one or more symptoms of a cancer in the subject. Non-limiting examples of symptoms of a cancer include fever, fatigue, pain, hyperpigmentation, jaundice, erythema, pruritis, excessive hair growth, long-term constipation, diarrhea, change in the size of stool, pain when urinating, blood in urine, change in bladder function, sore that do not heal, w % bite patches inside the mouth or on tongue, unusual bleeding or discharge, indigestion, trouble swallowing, changes in warts, moles, or freckles, nagging cough, hoarseness, lump or area of thickening that can be felt under skin, weight changes, trouble breathing, discomfort after eating, persistent, unexplained muscle or joint pain, persistent, unexplained fevers and night sweats, and unexplained bruising. The diagnosis of a cancer by a health care profession (e.g., a physician) can also include performing laboratory tests (e.g., urine or blood tests, e.g., complete blood count), imaging tests (e.g., computerized tomography (CT), bone scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, ultrasound, and X-ray), and obtaining and/or examining a biopsy sample from the subject.

Exemplary methods of assisting in the diagnosis of a cancer in a subject and methods of predicting a subject's risk of developing a cancer are provided herein.

Trk Inhibitors

A variety of Trk inhibitors are known in the art. Non-limiting examples of Trk inhibitors are described below.

Non-limiting examples of Trk inhibitors are described in U.S. Pat. No. 8,513,263 and International Publication No. WO 2010/048314 both of which are incorporated by reference in their entireties herein, and include a compound of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein:

R¹is H or (1-6C alkyl);

R²is NR^bR^c, (1-4C)alkyl, (1-4C)fluoroalkyl, CF₃, (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr¹, -(1-4C alkyl)NH₂, -(1-4C alkyl)NH(1-4C alkyl), -(1-4C alkyl)N(1-4C alkyl)₂, hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl), or (3-6C)^ecycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMe, NH₂, NHMe, N(CH₃)₂·F, CF₃, CO₂(1-4C alkyl), CO₂H, C(═O)NR^bR^for C(═O)OR^g;

R^bis H or (1-6C alkyl);

R^cis H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr¹, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF₃and —O(1-4C alkyl),

or NR^bR^cforms a 4 membered heterocyclic ring having a ring nitrogen atom wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH₂, —NHC(═O)O(1-4C alkyl) and (1-4C)hydroxyalkyl,

or NR^bR^cforms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF₃, (1-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(═O)O(1-4C alkyl) and oxo,

or NR^bR^cforms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO₂(1-4C alkyl);

hetAr¹is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

hetAr²is 5-6 membered heteroaryl ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 C)alkoxy, and NH(1-4C alkyl);

hetCyc¹is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), and CO₂(1-4C alkyl);

hetCyc²is a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (1-4C)alkyl;

hetAr³is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (1-4C)alkyl;

R^eis H or (1-4C)alkyl;

R^fis H, (0-4C)alkyl, or (3-6C)cycloalkyl;

or NR^eR^fforms a 5-6-membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH;

R^gis H or (1-6C)alkyl;

Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF₃and CHF₂, or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms;

X is null, —CH—, —CH₂CH₂—, —CH₂O— or —CH₂NR^d—;

R^dis H or (1-4C alkyl);

R³is H or (1-4C alkyl);

each R⁴is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and

n is 0, 1, 2, 3, 4, 5 or 6.

For example, a Trk inhibitor can include one or more compounds selected from the group consisting of:

(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;
N-(5-(2-(3-fluorophenyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;
(R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-phenylurea;
(R)—N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;
(R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide;
(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;
(3R4R)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide;
(S)—N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide;
(R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;
(R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide; and
(R)-1-(4-chlorophenyl)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)urea,
or a pharmaceutically acceptable salt thereof.

In some embodiments, a Trk inhibitor can be (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate. For example, a Trk inhibitor can be a polymorph such as those described in U.S. Publication No. 2016/0137654 and International Publication No. WO 2016/077841, both of which are incorporated by reference in their entireties herein. Additional disclosure relating to Trk inhibitors can be found, for example, in U.S. Provisional Application Nos. 62/329,653, 62/329,561, and 62/338,359, all of which are incorporated by reference in their entireties.

Additional examples of Trk inhibitors are the macrocyclic compounds described in U.S. Pat. No. 8,933,084 and International Publication No. WO 2011/146336, both of which are herein incorporated by reference in their entireties. For example, Trk inhibitors include compounds of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein:

ring A is selected from rings A-1, A-2, and A-3 having the structures:

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wherein the wavy line labeled 1 indicates the point of attachment of ring A to ring B and the wavy line labeled 2 indicates the point of attachment of ring A to W;

X is N or CH;

Y is H or F;

R¹is H, (1-3C)alkoxy, or halogen;

ring B is selected from rings B-1 and B-2 having the structures:

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wherein the wavy line labeled 3 indicates the point of attachment to ring A and the wavy line labeled 4 indicates the point of attachment to the pyrazolo[1,5-a]pyrimidine ring of Formula I;

W is O, NH, or CH₂, wherein when ring A is A-2, then W is CH₂;

m is 0, 1, or 2;

D is carbon, R²and R^2aare independently H, F, (1-3 C)alkyl or OH (provided that R²and R^2aare not both OH), and R³and R³³are independently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl, or

D is carbon or nitrogen, R²and R³are absent, and R^2aand R^3atogether with the atoms to which they are attached form a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms;

Z is *—NR^4aC(═O)—, *—ONHC(═O)—, *—NR^4bCH₂— or *—OC(═O)—, wherein the asterisk indicates the point of attachment of Z to the carbon bearing R³;

R^4ais H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), or dihydroxy(2-6C alkyl);

R^4bis H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), dihydroxy(2-6C alkyl), (1-6C alkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar¹C(O)—, HOCH₂C(O)—, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar²(SO₂)—, HO₂CCH₂—, or (1-6C alkyl)NH(CO)—;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and

R⁵and R⁶are independently H, halogen, OH, (1-6C)alkyl, or hydroxy(1-6C)alkyl.

For example, a Trk inhibitor can include one or more compounds selected from the group consisting of:

(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^2.6.0^7,12.0^22,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^2,6.0^7,12.0^22,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^2,6.0^7,12.0^22,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^2,6.0^7,12.0^23,27]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;
(6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.1^7,11.0^2,6.0^20,24]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;
(6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0^2,6.0^7,12.0^22,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^2,6.0^7,12.0^22,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^2,6.0^7,12.0^22,26]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;
(6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25-]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-(15R)-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one:
(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25-]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
(6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.0^2,6.0^7,12.0^22,26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one; and
(6R)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^2,6.0^7,12.0^21,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;
or a pharmaceutically acceptable salt thereof.

Additional examples of Trk inhibitors are the substituted pyrazolo[1,5-a] pyrimidine compounds described in U.S. Pat. No. 8,791,123 and International Publication No. WO 2011/006074, both of which are herein incorporated by reference in their entireties. For example, Trk inhibitors that can include compounds of Formula I:

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or a pharmaceutically acceptable salt thereof,

wherein:

R¹is H or (1-6C alkyl);

R²is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl, -(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂, -(1-6C alkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr², hetAr², hetCyc², —O(1-6C alkyl) which is optionally substituted with halogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc¹, -(1-6C alkyl)(3-6C cycloalkyl), -(1-6C alkyl)(1-4C alkoxy), -(1-6C hydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ring optionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8 membered heterocyclic ring having 1-2 ring nitrogen atoms;

or NR¹R²forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, OH, CO₂H, (1-3C alkyl)CO₂H, —O(1-6C alkyl), and (1-6C)hydroxyalkyl;

hetCyc¹is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc¹is optionally substituted with oxo, OH, halogen, or (1-6C)alkyl;

hetCyc²is a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc²is optionally substituted with F, SO₂NH₂, SO₂(1-3C alkyl), or halogen;

hetAr¹is a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-4C)alkyl;

hetAr²is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen, and OH;

Cyc¹is a 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO₂H, -(1-4C alkyl)OH, halogen, and CF₃;

Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF₃, —CHF₂, —O(1-4C alkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein the heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl, and NH₂, or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl;

hetCyc³is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl;

X is —CH₂—, —CH₂CH₂—, —CH₂O—, or —CH₂NR^d—;

R^dis H or -(1-4C alkyl);

R³is H or -(1-4C alkyl);

each R⁴is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl), and —CH₂OH; and

n is 0, 1, 2, 3, 4, 5, or 6.

For example, a Trk inhibitor can include one or more compounds selected from the group consisting of:

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
N-((2S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(2-oxoimidazolidin-1-yl)ethyl)pyrazole[1,5-a]pyrimidine-3-carboxamide;
5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((R)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)—N-tert-butyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and
5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
or a pharmaceutically acceptable salt thereof.

Additional examples of Trk inhibitors are the substituted imidazo[1,2-b]pyridazine compounds described in U.S. Pat. No. 8,450,322 and International Publication No. WO 2010/033941, both of which are herein incorporated by reference in their entireties. For example, Trk inhibitors can include compounds of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein:

R¹is H or (1-6C alkyl);

R²is NR^bR^c, (1-4C)alkyl, (1-4C)fluoroalkyl, CF₃, (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr¹, -(1-4C alkyl)NH(1-4C alkyl), hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF₃, CO₂(1-4C alkyl) or CO₂H:

R^bis H or (1-6C alkyl);

R^cis H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr³, or phenyl, wherein said phenyl IS optionally substituted with one or more substituents independently selected from halogen, CN, CF3 and —O(1-4C alkyl),

or NR^bR^cforms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen. OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH₂, —NHC(═O)O(1-4C alkyl), and (1-4C)hydroxyalkyl,

or NR^bR^cforms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O, and SO₂, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF3, (1-4C)alkyl, CO₂(1-4C alkyl), CO₂H, NH₂, NHC(═O)O(1-4C alkyl), and oxo,

or NR^bR^cforms a 7-8 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with CO₂(1-4C alkyl);

hetAr¹is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

hetCyc¹is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), CO₂H and CO₂(1-4C alkyl);

hetCyc²is a pyridinone or pyridazinone ring substituted with a substituent selected from (1-4C)alkyl;

Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF₃and CHF₂, or a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O—, or —CH₂NR^d—;

R^dis H or (1-4C alkyl);

R³is H or (1-4C alkyl);

each R⁴is independently selected from halogen, (1-4C)alkyl. OH, (1-4 C)alkoxy, NH₂, NH(1-4C alkyl), and CH₂OH; and

n is 1, 2, 3, 4, 5, or 6.

Additional Trk inhibitors can be found in U.S. Publication No. 2015/0166564 and WO 2012/158413, both of which are incorporated by reference in their entireties herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration;

R^a, R^b, R^cand R^dare independently selected from H and (1-3C)alkyl;

X is O, S or NH:

R¹is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl, hetAr⁵(CH₂)_0-1, or Ar⁵(CH₂)_0-1;

R²is H, F, or OH;

Y is a bond, —O— or —OCH₂—;

B is Ar¹, hetAr¹, 1-6C alkyl or (1-6C)alkoxy;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

hetAr¹is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected form (1-6C)alkyl, halogen, OH, CF₃, NH₂and hydroxy(1-2C)alkyl;

Ring C is formula C-1, C-2, or C-3

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R³is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar²is phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and hydroxymethyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

hetAr²is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R⁴is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, amino-carbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxyl-carbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)aminocarboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, (1-3C alkoxy)amino-carbonyl, hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3C trifluoroalkyl)pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy, isoindoline-1,3-dionyl(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolonyl;

hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar³is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), (1-3C)trifluoroalkyl, and methoxybenzyl; or a 9-10 membered bicyclic heteroaryl having 1-3 ring nitrogen atoms;

Ar⁴is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—:

R⁵is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl, or trifluoro(1-3C alky)amido; or

hetAr⁵is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O or S, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy and CF₃;

Ar⁵is phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CF₃O—, (1-4C)alkoxycarbonyl and aminocarbonyl;

R^3ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R^3bis hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (0-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl; and

R^5ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen, (0-6C)alkyl and hydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in International Publication No. WO 2014078454, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates thereof,

wherein;

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

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Y is H, halogen, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkyl [optionally substituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-6C)alkoxy [optionally substituted with 1-5 fluoros], CN, aminocarbonyl or (1-4C alkoxy)carbonyl;

R^a, R^band R^care independently selected from H, halogen, (1-3C)alkyl, (1-3C)alkoxy and CN;

B is NR¹, O, a bond, CR^dR^e, S or SO₂;

D is NR¹, O, a bond, CR^fR^g, S or SO₂;

E is NR¹, O, a bond, or CR^hR\S or SO₂.

F is CR^jR^k;

provided that the ring formed by B, D, E, and F together with the atoms to which they are attached contains at least five atoms and zero or one of B, D or E is NR¹or O;

G is CR^mRⁿ;

K is NR¹; R¹is (1-6C)alkyl [optionally substituted with one to five fluoros], (1-6C)cycloalkyl [optionally substituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;

R^d, R^e, R^f, R^g, R^h, R\R^jand R^kare independently H, OH, (1-6C)alkyl [optionally substituted with one to five fluoros], (3-6C)cycloalkyl [optionally substituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros], hydroxy(2-6C)alkyl [optionally substituted with one to five fluoros], (2-6C)cyanoalkyl, (1-6C)alkoxy optionally substituted with one to five fluoros, or (1-3C alkoxy)(2-6C)alkoxy [optionally substituted with one to five fluoros], or one of a pair of R^dand R^e, or R^fand R^g, or R^hand R^l, or R* and R^k, together with the carbon atom to which they are attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring, or one of a pair of R^dand R^e, or R^fand R⁸, or R^hand R^l, or R^jand R^kform an oxo group, and wherein only one of R^dand R^ecan be OH and neither is OH if B is connected to a heteroatom, and only one of R^fand R^gcan be OH and neither is OH if D is connected to a heteroatom, and only one of R^hand R′ can be OH and neither is OH if E is connected to a heteroatom, and only one of R^jand R^kcan be OH and neither is OH if F is connected to a heteroatom;

R^mis H, (1-3C)alkyl [optionally substituted with 1-5 fluoros], cyclopropyl or cyclobutyl, and

R″ is H or (1-3C)alkyl [optionally substituted with 1-5 fluoros], or

R^mand Rⁿtogether form an oxo group:

R^pis H, (1-6C)alkyl [optionally substituted with one to five fluoros], (3-6C)cycloalkyl [optionally substituted with one to five fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one to five fluoros], hydroxy(2-6C)alkyl [optionally substituted with one to five fluoros], or (2-6C)cyanoalkyl;

Ring C is formula C-1 or C-2

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R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar²is phenyl optionally substituted with one or more groups independently selected from halogen and (1-6C)alkyl; hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

R⁴is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3 C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (0-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr⁵or hetCyc⁴-0-:

hetCyc³is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl; hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar³is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵is a group selected from the structures:

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where R^zis (3-4C)cycloalkyl or (1-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr⁵groups is optionally further substituted with one or more groups independently selected from F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

hetCyc⁴is a 7-8 membered bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

Ar¹is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—:

R⁵is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy); or R⁴and R⁵together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R⁴and R⁵together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO₂;

R^3ais halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^5ais halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in International Publication No. WO 2014078417, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein;

X is O, S, NH or N—CN;

Ring A is

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R¹is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl;

R²is (1-3C)alkyl [optionally substituted with 1 to 5 fluoros] or (3-4C)cycloalkyl [optionally substituted with one or two fluoros];

R¹is H or CHs;

Ring C is formula C-1 or C-2

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R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

hetAr²is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen; R⁴is hetAr⁴, hetAr⁵or hydroxy(1-6C)alkoxy;

hetAr¹is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr^eis a group selected from the structures:

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where R^zis (3-4C)cycloalkyl or (1-3Calkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr⁵groups is optionally further substituted with one or more substituents independently selected from F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

R⁴and R⁵together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)0-, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO₂; R is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen:

R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF3O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^5ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen.

Additional examples of Trk inhibitors can be found in International Publication No. WO 2014078408, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein;

X is O, S, NH or —N—CN;

Ring A is formula A-1 A-2, A-3 or A-4

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R¹is H, halogen, (1-3C)alkyl [optionally substituted with 1-5 fluoros], (1-3C)alkoxy [optionally substituted with 1-5 fluoros], or (3-5C)cycloalkyl;

Y is Ar¹or hetAr¹;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-3C)alkyl [optionally substituted with 1-5 fluoros], and (1-3C)alkoxy [optionally substituted with 1-5 fluoros];

hetAr¹is pyridyl optionally substituted with one or more substituents independently selected from halogen, (1-3C)alkyl [optionally substituted with 1-5 fluoros], and (1-3C)alkoxy [optionally substituted with 1-5 fluoros];

Ring C is formula C-1 or C-2

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R¹is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar¹, hetCyc¹, (3-7C)cycloalkyl, or hetAr²; Ar is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl; hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

R⁴is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴-0-, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)0-, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl; AT³is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁵is a group selected from the structures:

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where R^zis (3-4C)cycloalkyl or (1-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr⁵groups is optionally further substituted with one or more substituents independently selected from F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴is phenyl optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (0-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—;

R⁴and R⁵together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R⁴and R⁵together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)0-, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO₂;

R^3ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen;

R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-31C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^5ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in International Publication No. WO 2014078378, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^a, R^b, R^cand R^dare independently selected from H and (1-3C)alkyl, or R^cand R^dare independently selected from H and (1-3C)alkyl, and R^aand R^btogether with the atom to which they are attached form a cyclopropyl ring;

X is O, S, NH or N—CN;

R¹is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, or hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl;

R²is H, F, or OH;

Ring B is Ar¹or hetAr¹;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, CF₃, CF₃0-, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

hetAr¹is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, OH, CF₃, NH₂and hydroxy(1-2C)alkyl;

Ring C is selected from formulas C-1 through C-13:

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R is H, NH₂, CN, halogen, (1-3C)alkyl [optionally substituted with 1 to 3 fluoros],

H₂NC(═O)—, (1-3Calkyl)NHC(═O)—, di(1-3Calkyl)NHC(═OK hydroxy(1-3C)alkyl, CH3OCH2CH2, (3-4C)cycloalkyl or (1-3C)alkoxy:

R^3ais H, (1-3C)alky, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂, HOCH₂CH₂, MeOCH₂CH₂, or (3-4C)cycloalkyl;

R⁴is H, OH, (1-6C)alkyl [optionally substituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxy carbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar(1-6C)alkyl, (1-6C)alkoxy [optionally substituted with 1-5 fluoros], cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc (1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy. (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴-0-, Ar, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3 C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

R^4ais H, (1-6C)alkyl, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3 C alkoxy)(1-6C)alkyl], hetAr⁴, Ar⁴, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, hetCyc³, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F. CN, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴is independently a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (1-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, CN, hydroxy(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵is a group selected from the structures:

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Ar⁴is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—;

R⁵is H, (1-6C)alkyl [optionally substituted with 1-5 fluoros], halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy];

R^5ais H, (1-6C)alkyl, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (3-4C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy]:

R is (1-6C)alkyl, (3-6C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl, and trifluoro(1-3C)alkylamido];

R^8aand R^8bare independently H, halogen, CN, NH₂, (1-6C)alkyl [optionally substituted with 1-5 fluoros], (1-6C)alkoxy, (1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (1-6Calkyl)NH—, phenyl [optionally substituted with (1-6C alkyl)SO₂-] or hetAr⁴, wherein only one of R^8aand R^8bcan be phenyl [optionally substituted with (1-6C alkyl)SO₂-] or hetAr⁴;

R⁹is H, (1-6C)alkyl, CF₃CH₂—, CF₃CH₂CH₂—, (1-3Calkoxy)(1-6C)alkyl or (3-4C)cycloalkyl; and

R¹⁰is (3-6C)cycloalkyl or phenyl [optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl and trifluoro(1-3C alkyl)amido].

Additional examples of Trk inhibitors can be found in International Publication No. WO 2014078372, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula L:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^a, R^b, R^oand R^dare independently selected from H and (1-3C)alkyl,

or R^cand R^dare independently selected from H and (1-3C)alkyl, and R^aand R^btogether with the atom to which they are attached form a cyclopropyl ring;

X is O, S, NH or N—CN;

R¹is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3C)alkylamino(1-3C)alkyl, (1-4C) alkoxycarbonyl(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, or hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl;

R²is H, F, or OH;

Ring B is Ar¹or hetAr¹;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, CF₃, CF₃0-, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; hetAr¹is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, OH, CF₃, NH₂and hydroxy(1-2C)alkyl;

Ring C is selected from formulas C-1 through C-9

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R is H, halogen, or phenyl [optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl];

R^7aand R^7bare independently H, (1-6C)alkyl, or phenyl [optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl], wherein only one of R^7aand R^7bcan be phenyl optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl;

R⁸is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-3C)alkyl and (3-6C)cycloalkyl;

R⁹is H, halogen, (1-6C)alkyl [optionally substituted with one to five fluoros] or (1-6C)alkoxy; and

R¹⁰is H or (1-6C)alkyl.

Further examples of Trk inhibitors can be found in International Publication No. WO 2014078331, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I-C:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein;

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

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wherein the dashed lines are optional double bonds;

n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A is formula A-2;

G¹, G²and G³are independently CR^Xor N, wherein no more than 2 of G¹, G²and G³can be N;

each R^xis independently H, halogen, (1-4C)alkyl or (1-4C)alkoxy;

R¹is H, halogen, (1-3C)alkoxy(1-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl(1-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C)alkyl (optionally substituted with 1-5 fluoros), (1-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3C alkyl)sulfanyl (optionally substituted with 1-5 fluoros), cyano(1-3C)alkyl (optionally substituted with 1-5 fluoros), hydroxy(1-3C)alkyl (optionally substituted with 1-5 fluoros), (1-4C)alkyl (optionally substituted with 1-5 fluoros), CH₃CH₂NR^y, CF₃CH₂NR, HCF₂CH₂NR^y, H₂CFCH₂NR^y, CH₃NR^yCH₂, R^yR^yNCH₂CH₂, R^yR^yNCH₂CFH, or

R^yR^yNCH₂CF₂;

each R^yis independently H or methyl;

when n is 0, R is selected from the group consisting of H, halogen, (1-6C)alkyl

[optionally substituted with 1-5 fluoros], (1-6C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkoxy)(1-4C)alkyl, (3-6C cycloalkyl)CH₂0-, amino(1-3C)alkyl,

CF₃CH₂NHCH₂, HCF₂CH₂NHCH₂, a C5-C8 bridged cycloalkyl, hetCyc³, hetCyc^aCH₂, Cyc^a, hetAr¹and Ar¹, and

when n is 1, R is selected from the group consisting of H, halogen, CF₃, F₂CH, FCH₂, methyl and methoxy,

hetCyc³is a 4-6 membered heterocyclic ring having a ring heteroatom selected from N, O and S and optionally substituted with 1-3 groups independently selected from OH, F, (1-6C)alkoxy or (1-6C)alkyl [optionally substituted with 1-3 fluoros];

Cyc^ais a (3-6C)cycloalkyl optionally substituted with (1-4C)alkoxy, (1-4C)alkyl, F or

OH;

hetAr¹is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (1-6C)alkyl, halogen, OH, CF₃, NH₂and hydroxy(1-2C)alkyl;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, CF₃, CF₃0-, (1-4C)alkoxy, (1-4C)sulfanyl, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

R^ais H, (1-3C)alkyl, cyclopropyl, cyclobutyl, or CF₃, and

R^bis H, methyl or ethyl,

or R^aand R^btogether with the carbon atom to which they are attached form a 3-6 membered cycloalkyl ring;

R^cis H, methyl or ethyl

R^dis CF₃CH₂CH₂, phenyl or phenylCH₂— wherein each phenyl ring is optionally substituted with one or more substituents independently selected from halogen, methoxy and methoxymethyl;

Ring C is formula C-1 or C-2

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R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, a C5-C8 bridged cycloalkyl, or hetAr²;

Ar²is phenyl optionally substituted with one or more groups independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R⁴is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3 C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr, Ar⁴-0-, hetCyc⁴-0-, Cyc′-O—, or aminohydroxy(1-6C)alkoxy; hetCyc²is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (1-6C)alkyl, 1-4C alkoxy)carbonyl, (1-6C)acyl, halogen and oxo;

hetCyc⁴is a 5-8 membered monocyclic, spirocyclic or bridged heterocycle having a ring nitrogen atom and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

Cyc¹is a 3-6 membered carbocycle optionally substituted with an amino group; hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁵is a group selected from the structures:

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R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

Additional examples of Trk inhibitors can be found in International Publication No. WO 2014078328, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I-1:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

Ring A is selected from formulas A-1, A-2, A-3 or A-4:

text missing or illegible when filed

R¹is H, halogen, (1-3C)alkoxy(1-3C)alkyl [optionally substituted with 1-5 fluoros], (1-3C alkyl)sulfanyl(1-3C)alkyl [optionally substituted with 1-5 fluoros], (1-3C)alkoxy [optionally substituted with 1-5 fluoros], (1-3C alkyl)sulfanyl [optionally substituted with 1-5 fluoros], cyano(1-3C)alkyl [optionally substituted with 1-5 fluoros], hydroxy(1-3C)alkyl [optionally substituted with 1-5 fluoros]. (1-4C)alkyl [optionally substituted with 1-5 fluoros], CH₃CH₂NR^a, CF₃CH₂NR^a, HCF₂CH₂NR^a. H₂CFCH₂NR^a, CH₃NR^aCH₂, R{circumflex over ( )}{circumflex over ( )}CH₂CHs or R{circumflex over ( )}{circumflex over ( )}CH₂CFz;

each R^ais independently H or methyl;

R^xand R^yare independently selected from H, halogen, (1-3C)alkyl [optionally substituted with 1-5 fluoros] or (1-3C)alkoxy [optionally substituted with 1-5 fluoros];

n is 0, 1 or 2;

m is 0, 1 or 2;

X is O, S, NH or N—CN;

Ring C is formula C-1 or C-2

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R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

R⁴is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴-0-, Ar, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (I-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr;

hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, and (1-6C)acyl; hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl; hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar³is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy. (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵is a group selected from the structures:

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R⁵is (0-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy); or

R⁴and R⁵together with the atoms to which they are attached form a 5-6 membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R⁴and R⁵together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(-0)0-, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO₂;

R^4ais (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

Further examples of Trk inhibitors can be found in International Publication No. WO 2014078325, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

Ring A is formula A-1, A-2, A-3, A-4, A-5 or A-6

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m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

p is 0, 1 or 2;

R¹is formula R¹-1, R¹-2 or R¹-3

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Y¹is CH₃CH₂—, CF₃CH₂—, CH₃0-, F₃CO—, F₂CHO—, FCH₂0-, CH₃S—, F₃CS—, F₂CHS—, or FCH₂S—;

Y²is O, S, NH, MeN— or CH₂;

Y³is CH3O—, CH₃S—, MeNH— or Me₂N—;

Y⁴is CH₂and Y⁵is S or O, or Y⁴is S or O and Y is CH₂;

R²is halogen, (1-3C)alkyl (optionally substituted with 1-3 fluoros), (1-3C)alkoxy (optionally substituted with 1-3 fluoros), CH₃OCH₂— (optionally substituted with 1-3 fluoros), (1-3C alkyl)sulfanyl, di(1-3C)alkylamino, cyclopropyl, cyclobutyl or azetidinyl, wherein each of said cyclopropyl, cyclobutyl and azetidinyl is optionally substituted with 1 to 2 fluoros;

X is O, S, NH or N—CN;

Ring C is formula C-1 or C-2

text missing or illegible when filed

R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar²is phenyl optionally substituted with one or more groups independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

R⁴is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴-0-, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc, halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr;

hetAr³is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁵is a group selected from the structures:

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where R⁷is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr⁵groups is optionally further substituted with one or more groups independently selected from F and (1-3C)alkyl optionally substituted with 1-3 fluoros; AT⁴is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—;

R^4ais (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy(1-3 C)trifluoroalkyl; and R^ais (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen.

Additional examples of Trk inhibitors can be found in International Publication No. WO 2014078323, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula I:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^a, R^b, R^cand R^dare independently selected from H and (1-3C)alkyl,

or R^oand R^dare independently selected from H and (1-3C)alkyl, and R^aand R^btogether with the atom to which they are attached form a cyclopropyl ring;

X is O, S, NH, or N—CN;

R¹is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl or hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl;

R²is H, F, or OH;

Ring B is Ar¹or hetAr¹;

Ar¹is phenyl optionally substituted with one or more substituents independently selected from halogen, CF₃, CF₃0-, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; hetAr¹is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, OH, CF₃, NH₂and hydroxy(1-2C)alkyl;

Ring C is

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R³is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, hetAr², or a C5-C8 bridged carbocyclic ring;

Ar²is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O;

R⁴is selected fro -6C alkyl)SO₂—, (1-6C alkyl)C(═O)— and from the structures:

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R^mis (1-3C)alkyl substituted with 1-3 fluoros, or (3-4C)cycloalkyl;

Rⁿis (1-3C)alkyl;

R^qis (1-3C)alkyl optionally substituted with 1-3 fluoros;

R^xis (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂—, (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, trifluoro(1-3C)alkoxy or trifluoro(1-6C)alkyl;

n is, 1, 2,3 or 4;

m is 0, 1, 2 or 3;

R^yis F or (1-3C)alkyl optionally substituted with 1-3 fluoros;

p is 0, 1 or 2;

R^zis (3-4C)cycloalkyl, or (1-3C)alkyl optionally substituted with 1-3 fluoros; and R⁵is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylsulfanyl, phenyl [optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl, or trifluoro(1-3 C alkyl)amido.

Additional examples of Trk inhibitors can be found in International Publication No. WO 2014078322, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula L:

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or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein;

X is O, S, NH or N—CN:

Ring A is

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D is O or S;

R¹is phenyl optionally substituted with one or more substituents independently selected from halogen and (1-3C)alkyl;

R is (1-6C)alkyl [optionally substituted with 1 to 5 fluoros] or (3-6C)cycloalkyl [optionally substituted with one or two fluoros];

Ring C is formula C-1 or C-2

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R³is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, or hetAr²;

Ar is phenyl optionally substituted with one or more groups independently selected from halogen and (1-6C)alkyl;

hetCyc¹is a 5-6-membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; hetAr²is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen;

R⁴is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F. OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴—O—, Ar, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3 C)alkylsulfonamido(1-6C)alkoxy, (1-3 C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (I-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc²is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, and (1-6C)acyl; hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F. CN, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-31C trifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵is a group selected from the structures:

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Ar⁴is phenyl optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6C alkyl)OC(O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—;

R⁴and R⁵together with the atoms to which they are attached form 5-6 membered saturated, partially unsaturated or unsaturated heterocyclic ring having a ring heteroatom selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionally oxidized to S(═O) or SO₂; ^3ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen:

R^4ais hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃0-, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^5ais hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted with one or more substituents independently selected from halogen and (1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in International Publication No. WO 2015175788, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a chloride salt.

Exemplary Trk inhibitors include AR-772, AR-786, AR-256, and AR-618.

Non-limiting examples of Trk inhibitors can be found in U.S. Pat. No. 8,299,057 and International Publication No. WO 2009/013126 both of which are incorporated by reference in their entireties. For example, a Trk inhibitor can be a compound of Formula (I):

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wherein;

X is —CH₂—, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein:

R′ is C₁-C₆alkyl and R″ is hydrogen;

Ar is phenyl, pyrazolyl or pyridyl optionally substituted with one or more substituents independently selected from halogen, nitro, COR4, OR7, NR5R6, NHSO₂R10, a straight or branched C₁-C₆alkyl optionally substituted by a heterocyclyl, in its turn optionally substituted by a straight or branched C₁-C₆alkyl or an heterocyclylalkyl, or a heterocyclyl optionally substituted by a straight or branched C₁-C₆alkyl, in its turn optionally substituted by a heterocyclyl or a C₁-C₆alkoxycarbonyl, or a C₁-C₆dialkylamino:

R4 is NR5R6, or a heterocyclyl, optionally further substituted by a straight or branched C₁-C₆alkyl, heterocyclylalkyl, heterocyclyl or a C₁-C₆dialkylamino;

R5 and R6 are independently hydrogen, R8R9N—C₂-C₆alkyl, R8O—C₂-C₆alkyl, a straight or branched C₁-C₆alkyl optionally further substituted by C₁-C₆alkoxy, C₁-C₆dialkylamino, halogen, phenyl, hydroxyl or heterocyclyl in its turn optionally substituted by alkyl, C₃-C₆cycloalkyl optionally substituted by hydroxyl or trifluoro C₁-C₆alkyl, heterocyclyl optionally substituted by C₁-C₆alkyl in its turn optionally substituted by halogen or heterocyclyl, C₁-C₆alkoxycarbonyl, C₁-C₆dialkylamino, heterocyclyl, or phenyl,

or R5 and R6, taken together with the nitrogen atom to which they are bonded, may form a heterocyclyl group optionally substituted by a straight or branched C₁-C₆alkyl, in its turn optionally substituted by a heterocyclyl or a C₁-C₆alkoxycarbonyl, a C₁-C₆dialkylamino or a heterocyclyl;

R7 is straight or branched C₁-C₆alkyl, optionally substituted by C₁-C₆dialkylamino or heterocyclyl in its turn substituted by C₁-C₆alkyl;

R8 and R9 are independently an optionally further substituted straight or branched C₁-C₆alkyl;

R10 is an optionally further substituted straight or branched C₁-C₆alkyl;

R is phenyl or pyridyl optionally substituted halogen or straight or branched C₁-C₆alkyl;

R1, R2 and R3 are hydrogen;

or optical isomers, tautomers or pharmaceutically acceptable salt thereof.

For example, a Trk inhibitor can be entrectinib (N-[5-(3,5difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide), or a pharmaceutically acceptable salt thereof. For example, a Trk inhibitor can be a polymorph such as those described in U.S. Publication No. 2015/0051222 or International Publication No. WO 2013/174876, both of which are incorporated by reference in their entireties herein. In some embodiments, a Trk inhibitor can be any disclosed in U.S. Publication No. 2015/0283132, International Publication No. WO 2015/124697, U.S. Pat. No. 8,946,226, International Publication No. WO 2010/012733. U.S. Pat. No. 8,912,194, and International Publication No. WO 2010/058006, all of which are incorporated by reference in their entireties herein.

Additional examples of Trk inhibitors can be found in International Publication No. WO 2015/017533, which is incorporated by reference in its entirety herein.

Further examples of Trk inhibitors can be found in International Publication No. WO 2015/112806, which is incorporated by reference in its entirety herein. For example, a Trk inhibitor can be a compound of Formula (I-A):

text missing or illegible when filed

or a pharmaceutically acceptable salt thereof, wherein:

Ring A′ and Ring B′ are each independently a monocyclic or bicyclic aryl or heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A′ and Ring B′ comprises at least one nitrogen ring member;

each L¹and L²is independently —C(R^1′)(R^2′)—, —O—, —N(R′)—, —S—, —S(O)— or —S(O)₂; each R¹and R²are independently H, deuterium, halogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl, —OR^a′, —OC(O)R^a′, —OC(O)NR^a′R^b′, —OS(O)R^a′, —OS(O)₂R^a′, —SR^a′, —S(O)R^a′, —S(O)₂R^a′, —S(O)NR^a′R^b′, —S(O)₂NR^a′R^b′, —OS(O)NR^a′R^b′, —OS(O)₂NR^a′R^b′, —NR^aR^b′, —NR^a′C(O)R^b′, —NR^a′C(O)OR^b′, —NR^a′C(O)NR^a′R^b′, —NR^a′S(O)R^b′, —NR^a′S(O)₂R^b′, —NR^a′S(O)NR^a′R^b′, —NR^a′S(O)₂NR^a′R^b′, —C(O)R^a′, —C(O)OR^a′, —C(O)NR^a′R^b′, —PR^a′R^b′, —P(O)R^a′R^b′, —P(O)₂R^a′R^b′, —P(O)NR^a′R^b′, —P(O)₂NR^a—R^b′, —P(O)OR^a′, —P(O)₂OR^a′, —CN, or —N0₂; or R^1′and R^2′ taken together with the carbon or carbons to which they are attached form a C_3-6cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein each hydrogen atom in C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, —OR^e′, —OC(O)R^e′, —OC(O)NR^e′R^f′, —OS(O)R^e′, —OS(O)₂R^e′, —OS(O)NR^e′R^f′, —OS(O)₂NR^eR^f, —SR^e′, —S(O)R^e′, —S(O)₂R^e′, —S(O)NR^e′R^f′, —S(O)₂NR^e′R^f′, —NR^e′R^f′, —NR^e′C(O)R^f′, —NR^e′C(O)OR^f′, —NR^e′C(O)NR^e′R^f′, —NR^e′S(O)R^f′, —NR^e′S(O)₂R^f′, —NR^e′S(O)NR^e′R^f′, —NR^e′S(O)₂NR^e′R^f′, —C(O)R^e″, —C(O)OR^e′, —C(O)NR^e′R^f′, —PR^e′R^f′, —P(O)R^e′R^f′, —P(O)₂R^e′R^f′, —P(O)NR^e′R^f′, —P(O)₂NR^e′R^f′, —P(O)OR^e′, —P(O)₂OR^e′, —CN, or —NO₂;

each R^k′is independently H, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, —Or^e′, —OC(O)R^e′, —OC(O)NR^e′R^f′, —OS(O)R^e′, —OS(O)₂R^e′, —OS(O)NR^e′R^f′, —OS(O)₂NR^e′R^f′, —SR^e′, —S(O)R^e′, —S(O)₂R^e′, —S(O)NR^e′R^f′, —S(O)₂NR^e′R^f′, —NR^e′R^f′, —NR^e′C(O)R^f′, —NR^e′C(O)OR^f′, —NR^e′C(O)NR^e′R^f′, —NR^e′S(O)R^f′, —NR^e′S(O)₂R^f′, —NR^e′S(O)NR^e′R^f′, —NR^e′S(O)₂NR^e′R^f′, —C(O)R^e′, —C(O)OR^e′, —C(O)NR^e′R^f′, —PR^e′R^f′, —P(O)R^e′R^f′, —P(O)₂R^e′R^f′, —P(O)NR^e′R^f′, —P(O)₂NR^e′R^f′, —P(O)OR^e′, —P(O)₂OR^e′, —CN, or —NO₂;

each R^3′and R^4′is independently deuterium, halogen, —OR^e′, —OC(O)R^e′, —OC(O)NR^c′R^d′, —OC(═N)NR^c′R^d′, —OS(O)R^c′, —OS(O)₂R^c′, —OS(O)NR^c′R^d′, —OS(O)₂NR^c′R^d′, —SR^c′, —S(O)R^c′, —S(O)₂R^c′, —S(O)NR^c′R^d′, —S(O)₂NR^c′R^d′, —NR^c′R^d′, —NR^c′C(O)R^d′, —NR^c′C(O)OR^d′, —NR^c′C(O)NR^c′R^d′, —NR^c′C(═N)NR^c′R^d′, —NR^c′S(O)R^d′, —NR^c′S(O)₂R^d′, —NR^c′S(O)NR^c′R^d′, —NR^c′S(O)?NR^c′R^d′, —C(O)R^c′, —C(O)OR^c′, —C(O)NR^c′R^d′, —C(═N)NR^c′R^d′, —PR^c′R^d′, —P(O)R^c′R^c′, —P(O)₂R^c′R^d′, —P(O)NR^c′R^d′, —P(O)₂NR^c′R^d′, —P(O)OR^c′, —P(O)₂OR^c′, —CN, —NO₂, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl, or any two R^3′groups or any two R^4′ groups taken together with the ring to which they are attached form a C_5-8cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each hydrogen atom in C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, mono- or bicyclic heteroaryl C_5-6cycloalkyl or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C_1-6alkyl, C_1-6haloalkyl, —OR^e′, —OC(O)R^e′, —OC(O)NR^e′R^f′, —OS(O)R^e′, —OS(O)₂R^e′, —OS(O)NR^e′R^f′, —OS(O)₂NR^e′R^f′, —SR^e′, —S(O)R^e′, —S(O)₂R^e′, —S(O)NR^e′R^f′, —S(O)₂NR^e′R^f′, —NR^e′R^f′, —NR^e′C(O)R^f′, —NR^e′C(O)OR^f′, —NR^e′C(O)NR^e′R^f′, —NR^e′S(O)R^f′, —NR^e′S(O)₂R^f′, —NR^eS(O)NR^e′R^f′, —NR^e′S(O)₂NR^e′R^f′, —C(O)R^e′, —C(O)OR^e′, —C(O)NR^e′R^f′, —PR^e′R^f′, —P(O)R^e′R^f′, —P(O)₂R^e′R^f′, —P(O)NR^e′R^f′, —P(O)₂NR^e′R^f′, —P(O)OR^E′, —P(O)₂OR^e′, —CN, or —NO₂;

R^7′ is H, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, —OR^i′, —OC(O)R^i′, —OC(O)NR^i′R^j′, —OS(O)R^i′, —OS(O)₂R^i′, —OS(O)NR^i′R^j′, —OS(O)₂NR^i′R^j′, —SR^i′, —S(O)R^i′, —S(O)₂R^i′, —S(O)NR^i′R^j′, —S(O)₂NR^i′R^j′, —NR^i′R^j′, —NR^i′C(O)R^j′, —NR^i′C(O)OR^i′, —NR^i′C(O)NR^i′R^j′, —NR^i′S(O)R^j′, —NR^i′S(O)₂R^j′, —NR^i′S(O)NR^i′R^j′, —NR^i′S(O)₂NR^i′R^j′, —C(O)R^i′, —C(O)OR^i′, —C(O)NR^i′R^j′, —PR^i′R^j′, —P(O)R^i′R^j′, —P(O)₂R^i′R^j′, —P(O)NR^i′R^j′, —P(O)₂NR^i′R^j′, —P(O)OR^i′, —P(O)₂OR^i′, —CN, or —NO₂;

each R^a′, R^b′, R^c′, R^d′, R^e′, R^f′, R^i′and R^j′ is independently selected from the group consisting of H, deuterium, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C_6-10aryl, and heteroaryl;

m′ is 2, 3, 4, or 5:

n′ is 2, 3, or 4;

p′ is 0, 1, 2, 3, or 4; and

q′ is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. Exemplary Trk inhibitors include TPX-0005.

A Trk inhibitor can be one found in U.S. Pat. No. 9,187,489 and International Publication No. WO 2013/183578, both of which are incorporated by reference in their entireties herein. Exemplary Trk inhibitors include PLX7486 and DS-6051.

Non-limiting examples of Trk inhibitors can be found in U.S. Publication No. 2015/0306086 and International Publication No. WO 2013/074518, both of which are incorporated by reference in their entireties herein. Exemplary Trk inhibitors include TSR-011.

Further examples of Trk inhibitors can be found in U.S. Pat. No. 8,637,516, International Publication No. WO 2012/034091, U.S. Pat. No. 9,102,671, International Publication No. WO 2012/116217, U.S. Publication No. 2010/0297115, International Publication No. WO 2009/053442, U.S. Pat. No. 8,642,035, International Publication No. WO 2009092049, U.S. Pat. No. 8,691,221, International Publication No. WO2006131952, all of which are incorporated by reference in their entireties herein. Exemplary Trk inhibitors include GNF-4256, described in Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and GNF-5837 (N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea), described in ACS Med. Chem. Lett. 3(2):140-145, 2012, each of which is incorporated by reference in its entirety herein.

Additional examples of Trk inhibitors include those disclosed in U.S. Publication No. 2010/0152219, U.S. Pat. No. 8,114,989, and International Publication No. WO 2006/123113, all of which are incorporated by reference in their entireties herein. Exemplary Trk inhibitors include AZ623, described in Cancer 117(6):1321-1391, 2011; AZD6918, described in Cancer Biol. Ther. 16(3):477-483, 2015; AZ64, described in Cancer Chemother. Pharmacol. 70:477-486, 2012; AZ-23 ((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine), described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451; each of which is incorporated by reference in its entirety.

A Trk inhibitor can include those described in U.S. Pat. Nos. 7,615,383; 7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and 5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors include CEP-751, described in Int. J. Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereol. 95:542-548, 2015; compounds described in International Publication No. WO 2012/034095; compounds described in U.S. Pat. No. 8,673,347 and International Publication No. WO 2007/022999; compounds described in U.S. Pat. No. 8,338,417; compounds described in International Publication No. WO 2016/027754; compounds described in U.S. Pat. No. 9,242,977; compounds described in U.S. Publication No. 2016/0000783; sunitinib (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide), as described in PLoS One 9:e95628, 2014; compounds described in International Publication No. WO 2011/133637; compounds described in U.S. Pat. No. 8,637,256; compounds described in Expert. Opin. Ther. Pat. 24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat. 19(3):305-319, 2009; (R)-2-phenylpyrrolidine substituted imadizopyridazines, e.g., (4-((5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone as described in ACS Med. Chem. Lett. 6(5):562-567, 2015; GTx-186 and others, as described in PLoS One 8(12):e83380, 2013; K252a ((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one), as described in Mol. Cell Biochem. 339(1-2):201-213, 2010; 4-aminopyrazolylpyrimidines, e.g., AZ-23 (((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)), as described in J. Med Chem. 51(15):4672-4684, 2008; PHA-739358 (danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Gö 6976 (5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile), as described in J. Neurochem. 72:919-924, 1999; GW441756 ((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one), as described in JAE 115:117, 2010; milciclib (PHA-848125AC), described in J. Carcinog. 12:22, 2013; AG-879 ((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide); altiratinib (N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); cabozantinib (N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); lestaurtinib ((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one); dovatinib (4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one mono 2-hydroxypropanoate hydrate); sitravatinib (N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide); ONO-5390556; regorafenib (4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate); VSR-902A; all of the references above are incorporated by reference in their entireties herein.

The ability of a Trk inhibitor to act as a TrkA, TrkB, and/or Trk C inhibitor may be tested using the assays described in Examples A and B in U.S. Pat. No. 8,513,263, which is incorporated herein by reference.

Methods of Treating a Subject Having a Cancer

Provided herein are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and administering to the identified subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein). Also provided are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and administering to the identified subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

Also provided are methods of treating a subject having a cancer (e.g., any of the cancers described herein) and identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) that include administering to the identified subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein). Also provided are methods of treating a subject having a cancer (e.g., any of the cancers described herein) and identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) that include administering to the identified subject a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

In some examples, the Trk inhibitor is administered orally, subcutaneously, intraperitoneally, intravenously, or intramuscularly. The Trk inhibitor can be administered in one or more doses comprising between about 1 mg and about 250 mg, between about 1 mg and about 200 mg, between about 1 mg and about 180 mg, between about 1 mg and about 160 mg, between about 1 mg and about 140 mg, between about 1 mg and about 120 mg, between about 1 mg and about 100 mg, between about 1 mg and about 80 mg, between about 1 mg and about 60 mg, between about 1 mg and about 40 mg, between about 1 mg and about 40 mg, between about 10 mg and about 200 mg, between about 10 mg and about 180 mg, between about 10 mg and about 160 mg, between about 10 mg and about 140 mg, between about 10 mg and about 120 mg, between about 10 mg and about 100 mg, between about 10 mg and about 80 mg, between about 10 mg and about 60 mg, between about 10 mg and about 40 mg, between about 10 mg and about 20 mg, between about 20 mg and about 200 mg, between about 20 mg and about 180 mg, between about 20 mg and about 160 mg, between about 20 mg and about 140 mg, between about 20 mg and about 120 mg, between about 20 mg and about 100 mg, between about 20 mg and about 80 mg, between about 20 mg and about 60 mg, between about 20 mg and about 40 mg, between about 40 mg and about 200 mg, between about 40 mg and about 180 mg, between about 40 mg and about 160 mg, between about 40 mg and about 140 mg, between about 40 mg and about 120 mg, between about 40 mg and about 100 mg, between about 40 mg and about 80 mg, between about 40 mg and about 60 mg, between about 60 mg and about 200 mg, between about 60 mg and about 180 mg, between about 60 mg and about 140 mg, between about 60 mg and about 120 mg, between about 60 mg and about 100 mg, between about 60 mg and about 80 mg, between about 80 mg and about 200 mg, between about 80 mg and about 180 mg, between about 80 mg and about 160 mg, between about 80 mg and about 140 mg, between about 80 mg and about 120 mg, between about 80 mg and about 100 mg, between about 90 mg and about 110 mg, between about 95 mg and about 105 mg, between about 100 mg and about 200 mg, between about 100 mg and about 180 mg, between about 100 mg and about 160 mg, between about 100 mg and about 140 mg, between about 100 mg and about 120 mg, between about 120 mg and about 200 mg, between about 120 mg and about 180 mg, between about 120 mg and about 160 mg, between about 120 mg and about 140 mg, between about 140 mg and about 200 mg, between about 140 mg and about 180 mg, between about 140 mg and about 160 mg, between about 160 mg and about 200 mg, between about 160 mg and about 200 mg, between about 160 mg and about 180 mg, or between about 180 mg and about 200 mg. The appropriate dose of a Trk inhibitor to be administered to a subject can be determined by a medical professional, e.g., based upon one or more of the subject's mass, the subject's condition, subject's gender, and the other diseases that the subject may have.

Multiple doses of a Trk inhibitor (e.g., any of the doses described herein) can be administered once every six months, once every five months, once every four months, once every three months, once every two months, once every six weeks, once a month, once every three weeks, once every two weeks, once a week, twice a week, three times a week, four times a week, three times a week, every other day, once a day, twice a day, or three times a day. The Trk inhibitor can be self-administered (e.g., by the subject having a cancer) or can be administered by a health care professional (e.g., a physician, a nurse, a physician's assistance, or a pharmacist). In some examples, the subject is hospitalized or treated on in inpatient basis. In other examples, the subject is treated on an outpatient basis.

The cancer can be any of the exemplary cancers described herein. In some embodiments, the subject has previously been identified or diagnosed as having a cancer. In some examples, the subject has previously been administered a treatment for cancer, and the treatment for cancer has been unsuccessful (e.g., high toxicity in the subject or no positive response to the previously administered treatment for cancer).

Some examples of these methods further include recording in the subject's clinical record (e.g., a computer readable medium) that the subject should be administered a treatment comprising a therapeutically effective amount of a Trk inhibitor in the future.

In some examples, the step of identifying a subject having a cancer cell that has the at least one point mutation (e.g., any of the point mutations described herein) in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein including a mutation at one or more amino acid position(s), comprises performing an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene in a cancer cell in a sample (e.g., a biopsy sample) from the subject. Any of the assays described herein can be used to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In addition, any of the kits provided herein can be used in an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In some examples, the assay includes sequencing a segment of a NTRK1, NTRK2, and/or NTRK3 gene including the at least one point mutation.

Methods of Selecting a Treatment for a Subject

Also provided herein are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for the identified subject. Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for the identified subject.

Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the cancers described herein) that include selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for a subject identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein). Also provided are methods of selecting a treatment for a subject having a cancer (e.g., any of the Trk inhibitors described herein) that include selecting a treatment comprising a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) for a subject identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M).

Some examples of these methods further include administering the selected treatment to the identified subject (e.g., using any of the Trk inhibitors, any of the routes of administration, any of the doses, and/or any of the frequencies of administration described herein). In some examples, the selected treatment is self-administered. In other examples, the selected treatment is administered by a medical professional (e.g., any of the medical professionals described herein). Some examples of these methods further include recording the selected treatment in the identified subject's clinical record (e.g., a computer readable medium).

Methods of Selecting a Subject for Treatment with a Trk Inhibitor

Also provided are methods of selecting a subject having a cancer for treatment with a Trk inhibitor that include identifying a subject having a cancer (e.g., any of the cancers described herein) and having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and selecting the identified subject for treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein). Also provided are methods of selecting a subject having a cancer for treatment with a Trk inhibitor that include identifying a subject having a cancer (e.g., any of the cancers described herein) and having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and selecting the identified subject for treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

Also provided are methods of selecting a subject having a cancer for treatment with a Trk inhibitor that include selecting a subject having cancer (e.g., any of the cancers described herein) and identified as having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) for treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein). Also provided are methods of selecting a subject having a cancer for treatment with a Trk inhibitor that include selecting a subject having a cancer (e.g., any of the cancers described herein) and identified as having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) for treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein).

Some examples of these methods further include administering a therapeutically effective amount of a Trk inhibitor (e.g., using any of the Trk inhibitors, any of the routes of administration, any of the doses, and/or any of the frequencies of administration described herein) to the selected subject. In some examples, the Trk inhibitor is self-administered. In other examples, the Trk inhibitor is administered to the selected subject by a medical professional. In some examples, the selected subject is hospitalized. In other examples, the subject is administered the Trk inhibitor on an outpatient basis. Some methods further include recording in the subject's clinical record (e.g., a computer readable medium) that the subject is selected for treatment with a Trk inhibitor.

Methods of Determining the Likelihood that a Subject Will have a Positive Response to a Trk Inhibitor

Also provided are methods of determining the likelihood that a subject having a cancer (e.g., any of the cancers described herein) will have a positive response to treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and determining that a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTKR3 point mutations) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) has an increased likelihood of having a positive response to treatment with a Trk inhibitor (e.g., as compared to a subject having a cancer cell that does not have a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)). Also provided are methods of determining the likelihood that a subject having a cancer (e.g., any of the cancers described herein) will have a positive response to treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) and determining that a subject having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) has an increased likelihood of having a positive response to treatment with a Trk inhibitor (e.g., as compared to a subject having a cancer cell that does not have a point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Also provided are methods of determining the likelihood that a subject having cancer (e.g., any of the cancers described herein) will have a positive response to a treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining that a subject having a cancer cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) has an increased likelihood of having a positive response to treatment with a Trk inhibitor (e.g., as compared to a subject having a cancer cell that does not have at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)). Also provided are methods of determining the likelihood that a subject having cancer (e.g., any of the cancers described herein) will have a positive response to a treatment with a Trk inhibitor (e.g., any of the Trk inhibitors described herein) that include determining that a subject having a cancer cell that has at least one (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) has an increased likelihood of having a positive response to treatment with a Trk inhibitor (e.g., as compared to a subject having a cancer cell that does not have at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Some examples of these methods include administering a therapeutically effective amount of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) to a subject determined to have an increased likelihood of having a positive response to treatment with a Trk inhibitor (e.g., using any of the Trk inhibitors, any of the routes of administration, any of the doses, and/or any of the frequencies of administration described herein). In some examples, the Trk inhibitor is self-administered. In other examples, the Trk inhibitor is administered to the selected subject by a medical professional. In some examples, the selected subject is hospitalized. In other examples, the subject is administered the Trk inhibitor on an outpatient basis. Some methods further include recording in the subject's clinical record (e.g., a computer readable medium) that the subject has an increased likelihood of having a positive response to treatment with a Trk inhibitor.

In some examples, the step of determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA. TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), comprises performing an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene in a cancer cell in the sample (e.g., a biopsy sample) from the subject. Any of the assays described herein can be used to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In addition, any of the kits provided herein can be used in an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In some examples, the assay includes sequencing a segment of a NTRK1, NTRK2, and/or NTRK3 gene including the at least one point mutation.

Methods of Predicting the Efficacy of Treatment with a Trk Inhibitor in a Subject

Also provided are methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) in a subject having cancer (e.g., any of the cancers described herein) that include determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) (e.g., as compared to a subject having a cancer cell in a sample obtained from the subject that does not have a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)).

Also provided are methods of predicting the efficacy of a Trk inhibitor (e.g., any of the Trk inhibitors described herein) in a subject having cancer (e.g., any of the cancers described herein) that include determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314C A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and determining that a Trk inhibitor is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) (e.g., as compared to a subject having a cancer cell in a sample obtained from the subject that does not have a point mutation in a NTRK3 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Also provided are methods of predicting the efficacy of a Trk inhibitor in a subject having a cancer (e.g., any of the cancers described herein) that include determining that a Trk inhibitor (e.g., any of the Trk inhibitors described herein) is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) (e.g., as compared to a subject having a cancer cell in a sample obtained from the subject that does not have a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTKR3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA. TrkB, and/or TrkC described herein)).

Also provided are methods of predicting the efficacy of a Trk inhibitor in a subject having a cancer (e.g., any of the cancers described herein) that include determining that a Trk inhibitor (e.g., any of the Trk inhibitors described herein) is more likely to be effective in a subject having a cancer cell in a sample obtained from the subject that has at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of: 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G40R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) (e.g., as compared to a subject having a cancer cell in a sample obtained from the subject that does not have a mutation at one or more amino acid position(s) selected from the group consisting of; 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Some methods further include recording in the subject's clinical record (e.g., a computer readable medium) the predicted efficacy of a Trk inhibitor in the subject having a cancer. Some examples of these methods further include selecting a treatment for the subject based on the predicted efficacy of a Trk inhibitor in the subject. Some examples further include administering the selected treatment to the subject (e.g., using any of the Trk inhibitors, any of the routes of administration, any of the doses, and/or any of the frequencies of administration described herein).

Methods of Predicting the Risk of Developing a Cancer

Also provided are methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and identifying a subject having a cell that has at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) as having an increased likelihood of developing a cancer (e.g., as compared to a subject not having a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)).

Also provided are methods of identifying a determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) as having an increased likelihood of developing a cancer (e.g., as compared to a subject not having a point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Also provided are methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation(s) in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) as having an increased likelihood of developing a cancer (e.g., as compared to a subject having a cell that does not have a point mutation(s) in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)).

Also provided are methods of determining a subject's risk for developing a cancer (e.g., any of the cancers described herein) that include identifying a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation(s) in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), as having an increased likelihood of developing a cancer (e.g., as compared to a subject having a cell that does not have a point mutation(s) in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Some methods further include recording in the subject's clinical record (e.g., a computer readable medium) the subject's risk of developing a cancer. The cancer can be any of the exemplary cancers described herein.

In some examples, the subject is identified as having been exposed to a significant level of carcinogen(s) (e.g., tobacco smoke, UVB radiation, and gamma irradiation). In some examples, the subject is suspected of having cancer, presents with one or more symptoms of cancer (e.g., any of the symptoms of cancer described herein), and/or has a family history of cancer.

In some examples, the step of determining whether a cancer cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), comprises performing an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene in a cancer cell in the sample (e.g., a biopsy sample) from the subject. Any of the assays described herein can be used to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In addition, any of the kits provided herein can be used in an assay to determine the presence of the at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene. In some examples, the assay includes sequencing a segment of a NTRK1, NTRK2, and/or NTRK3 gene including the at least one point mutation.

Methods of Assisting in the Diagnosis of Cancer in a Subject

Also provided herein are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein), and determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) has an increased risk likelihood of having a cancer (e.g., as compared to a subject not having a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)).

Also provided herein are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) that include determining whether a cell in a sample obtained from the subject has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M), and determining that a subject having a cell that has at least one (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G40R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) has an increased risk likelihood of having a cancer (e.g., as compared to a subject not having a point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining that a subject having a cell that has at least one point mutation in a NTRK1, NTRK2, and/or NTRK3 gene (e.g., any of the NTRK1, NTRK2, and/or NTRK3 point mutations described herein) that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein) has an increased likelihood of having a cancer (e.g., as compared to a subject having a cell that does not have a point mutation in a NTRK1, NTRK2, and/or NTRK3 gene that results in the expression of a TrkA, TrkB, and/or TrkC protein comprising one or more mutations (e.g., any of the mutations in TrkA, TrkB, and/or TrkC described herein)).

Also provided are methods of assisting in the diagnosis of a cancer (e.g., any of the cancers described herein) in a subject that include determining that a subject having a cell that has at least one point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve) amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M) has an increased likelihood of having a cancer (e.g., as compared to a subject having a cell that does not have a point mutation in a NTRK2 gene that results in the expression of a TrkB protein comprising a mutation at one or more amino acid position(s) selected from the group consisting of 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 (e.g., one or more of the mutations of M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M)).

Some embodiments further include confirming the diagnosis of a cancer in a subject determined to have an increased likelihood of having a cancer. Confirming the diagnosis of a cancer in a subject can include, e.g., performing additional laboratory tests (e.g., urine or blood tests, e.g., complete blood count), imaging tests (e.g., computerized tomography (CT), bone scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, ultrasound, and X-ray), and/or physical examination to determine the presence of one or more symptoms of a cancer in the subject.

Some methods further include recording in the subject's clinical record (e.g., a computer readable medium) the subject's likelihood of having a cancer. The cancer can be any of the exemplary cancers described herein.

In some examples, the subject is identified as having been exposed to a significant level of carcinogen(s) (e.g., tobacco smoke. UVB radiation, and gamma irradiation). In some examples, the subject is suspected of having cancer, presents with one or more symptoms of cancer (e.g., any of the symptoms of cancer described herein), and/or has a family history of cancer.

Kits

Also provided herein are kits that include one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, or eighteen) probes that specifically hybridize to a segment of a NTRK1, NTRK2, and/or NTRK3 gene that comprises one of the point mutations described herein (e.g., any of the point mutations in NTRK1, NTRK2, and/or NTRK3 described herein). For example, the kits provided herein can include one or more probes that specifically hybridize to a segment of a NTRK2 gene that encodes a mutation at one of: amino acid positions 240, 241, 242, 264, 314, 315, 401, 426, 427, 428, 440, and 689 in TrkB protein (e.g., encodes a mutation selected from the group of: M240I, N241D, E242K, I264M, A314E, A314G, A314V, L315F, G401A, G401E, G401R, T426I, G427S, R428Q, A440S, A440T, A440V, and V689M in a TrkB protein).

Each of the one or more probes can have a length of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 nucleotides. In some embodiments, the one or more probes include a detectable label (e.g., a fluorophore, a quencher, a radioisotope, or a metal). In some embodiments, the one or more probes can be covalently attached to a substrate (e.g., a film, a plate, or a bead).

The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES
Example 1. Identification of TRK Point Mutations in Cancer Biopsy Samples

A set of experiments were performed to identify point mutations in NTRK1, NTRK2, and NTRK3 genes in biopsy samples from patients having a variety of different cancers.

Methods

One thousand eight hundred and twenty three mutations in NTRK1, NTRK2, and NTRK3 genes were identified in next-generation sequencing data from 42,155 tumor biopsy samples. Mutations that were synonymous, lead to loss of a canonical stop codon, cause truncation of the kinase domain, or are mapped to an alternative transcript that does not contain a full kinase domain were filtered out. All mutations within the given, preceding, and subsequent codons were clustered together. Duplicate clusters were then removed.

The mutation clusters were ranked for follow-up by combining several component scores into a single score via multiplication. The hotspot score captures the prevalence of the mutation cluster (size of the cluster/size of the largest cluster). The domain score captures the functional relevance of the protein region harboring the culture to oncogenesis (kinase domain=1, Ig-like domains=0.9, leucine-rich repeats=0.3, and none=0.05). The co-alteration score captures the likelihood that the mutation cluster contains drivers based on the presence of co-occurring mutations in other oncogenes. The exact score captures the rarity of the mutations in a large collection of germline samples, as a measure of relevance to oncogenesis. The conservation score captures how conserved the region of the protein is across placental mammals, as a measure of functional relevance.

Expression filtering was also used, after clustering, to confirm that at least one mutation in a given cluster be associated with expression of the relevant NTRK gene above background.

Structural modeling was performed by mapping specific amino acid residues onto a TrkB protein crystal structure (PDB entry 4ASZ) and a judgment was made on activation potential based on the structure and knowledge of kinase regulation.

Results

Point mutations in each of NTRK1, NTRK2, and NTRK3 were detected in biopsy samples from different patients having a variety of different cancers. Table 1 lists the point mutations identified in NTRK1, Table 2 lists the point mutations identified in NTRK2, Table 3 lists the point mutations identified in NTRK2 that have been confirmed to be expressed in cancer cells in the biopsy sample, and Table 4 lists the point mutations identified in NTRK3.

TABLE 1

Detected TrkA Protein Mutations Resulting from NTRK1 Point Mutations Detected in Cancer Biopsy Samples

Mutated
Mutations

Hotspot
Domain
co-Alteration
Exac
Conservation
Total

Samples
Ref. Transcript/Protein
Domain
Score
Score
Score
Score
Score
Score
Disease

4
R3P

0.2000
0.0500
1.0000
1.0000
0.4693
0.0047
Breast Carcinoma;

R3Q

Lung Squamous Cell

G4A

Carcinoma;

NM_002529

Unknown Primary

NP_002520

Carcinoma

8
A5T

0.4000
0.0500
0.0000
0.9016
0.3090
0.0000
Colon

A5V

Adenocarcinoma;

NM_001007792

Lung

NP_001007793

Adenocarcinoma;

Skin Melanoma

3
R6W

0.1500
0.0500
1.0000
0.0000
0.6577
0.0000
Prostate Carcinoma;

R7S

Uterus

G8E

Leiomyosarcoma;

NM_002529

Peritoneum

NP_002520

Mesothelioma

3
A10E

0.1500
0.0500
1.0000
1.0000
0.0000
0.0000
Colon

A10T

Adenocarcinoma;

NM_001007792

Lung Squamous Cell

NP_001007793

Carcinoma

1
V13I

0.0500
0.0500
1.0000
0.9836
0.4192
0.0000
Lung

NM_001007792

Adenocarcinoma

NP_001007793

1
W15C

0.0500
0.0500
1.0000
1.0000
0.9187
0.0023
Lung Squamous

NM_002529

Cell Carcinoma

NP_002520

1
A17T

0.0500
0.0500
1.0000
1.0000
0.0000
0.0000
Unknown Primary

NM_002529

Carcinoma

NP_002520

1
T18M

0.0500
0.0500
1.0000
1.0000
0.9970
0.0022
Liver Hepatocellular

NM_001007792

Carcinoma

NP_001007793

1
G20D

0.0500
0.0500
1.0000
0.9672
0.9968
0.0000
Kidney Renal Cell

NM_002529

Carcinoma

NP_002520

1
W22R

0.0500
0.0500
1.0000
1.0000
0.9909
0.0022
Liver Hepatocellular

NM_001007792

Carcinoma

NP_001007793

4
L22Q

0.2000
0.0500
1.0000
0.9344
0.9903
0.0000
Lung

NM_002529

Adenocarcinoma;

NP_002520

Kidney Renal Cell

Carcinoma;

Bone Chordoma

4
A24S

0.2000
0.0500
1.0000
1.0000
0.7401
0.0000
Colon

W25C

Adenocarcinoma;

NM_002529

Lung

NP_002520

Adenocarcinoma;

Stomach

Adenocarcinoma

1
S30P

0.0500
0.0500
1.0000
1.0000
0.9903
0.0000
Breast Carcinoma

NM_002529

NP_002520

1
R31I

0.0500
0.0500
1.0000
1.0000
0.9463
0.0021
Lung

NM_001007792

Adenocarcinoma

NP_001007793

3
A33S

0.1500
0.0500
1.0000
0.9672
0.7928
0.0010
Colon

A33V

Adenocarcinoma;

A34T

Breast Invasive

NM_002529

Ductal Carcinoma;

NP_002520

Soft Tissue

Paraganglioma

1
L38W

0.0500
0.0500
1.0000
1.0000
0.9909
0.0022
Kidney Renal

NM_001007792

Papillary Carcinoma

NP_001007793

2
D38N

0.1000
0.0500
1.0000
0.9836
0.8478
0.0011
Bladder Urothelial

A39S

Carcinoma;

NM_002529

Duodenum

NP_002520

Adenocarcinoma

3
C41W

0.1500
0.0500
0.0000
1.0000
0.7805
0.0000
Lung

P42T

Adenocarcinoma;

H43Q

Lung Small Cell

NM_002529

Undifferentiated

NP_002520

Carcinoma;

Uterus Endometrial

Adenocarcinoma

7
R49G

0.3500
0.0500
1.0000
0.9180
0.6369
0.0000
Breast Carcinoma;

R49P

Unknown Primary

R49Q

Adenocarcinoma;

C50Y

Uterus Endometrial

NM_002529

Adenocarcinoma

NP_002520

Endometrioid

2
R52L

0.1000
0.0500
1.0000
1.0000
0.0000
0.0000
Unknown Primary

R52Q

Melanoma;

NM_002529

Ovary Epithelial

NP_002520

Carcinoma

2
A55D

0.1000
0.0500
1.0000
1.0000
0.8122
0.0000
Pancreas Ductal

L56M

Adenocarcinoma;

NM_002529

Lymphoma Non-

NP_002520

Hodgkins

1
L59F

0.0500
0.0500
1.0000
1.0000
0.7258
0.0002
Unknown Primary

NM_002529

Adenocarcinoma

NP_002520

6
L62P

0.3000
0.0500
1.0000
0.8361
0.9893
0.0000
Lung

P63S

Adenocarcinoma;

NM_002529

Colon

NP_002520

Adenocarcinoma;

Prostate Acinar

Adenocarcinoma

1
E66D

0.0500
0.0500
1.0000
1.0000
0.9958
0.0025
Unknown Primary

NM_002529

Carcinoma

NP_002520

1
T69I

0.0500
0.0500
1.0000
1.0000
0.9289
0.0002
Lung

NM_002529

Adenocarcinoma

NP_002520

1
L71I

0.0500
0.0500
1.0000
1.0000
0.9348
0.0023
Lung

NM_002529

Adenocarcinoma

NP_002520

3
E74K

0.1500
0.0500
1.0000
0.9836
0.9959
0.0024
Colon

NM_002529

Adenocarcinoma;

NP_002520

Unknown Primary

Melanoma;

Kidney Sarcomatoid

Carcinoma

5
L79Q

0.2500
0.0500
1.0000
0.8033
0.7826
0.0000
Lung

Q80R

Adenocarcinoma;

NM_002529

Ovary Serous

NP_002520

Carcinoma;

Bone Marrow

Multiple Myeloma

6
R85C

0.3000
0.0500
0.1667
0.9016
0.1407
0.0002
Soft Tissue

D86N

Sarcoma;

D86Y

Lung

NM_002529

Adenocarcinoma;

NP_002520

Lung Non-Small Cell

Lung Carcinoma

5
R88K

0.2500
0.0500
1.0000
0.9508
0.8021
0.0055
Lung

R88S

Adenocarcinoma;

G89S

Colon

L90M

Adenocarcinoma;

L90del

Unknown Primary

NM_002529

Adenocarcinoma

NP_002520

4
G89S
LRR 1
0.2000
0.3000
1.0000
0.9180
0.7915
0.0418
Lung

L90M

Adenocarcinoma;

L90del

Colon

G91R

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Melanoma

4
L90M
LRR 1
0.2000
0.3000
1.0000
0.9672
0.6363
0.0350
Lung

L90del

Adenocarcinoma;

G91R

Colon

E92K

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Undifferentiated

Neuroendocrine

Carcinoma

2
L96V
LRR 1
0.1000
0.3000
1.0000
1.0000
0.9615
0.0268
Breast Ductal

T97I

Carcinoma in Situ;

NM_002529

Unknown Primary

NP_002520

Melanoma

3
S101C
LRR 1
0.1500
0.3000
1.0000
0.9836
0.9908
0.0185
Kidney Renal Cell

S101N

Carcinoma;

S101R

Unknown Primary

NM_002529

Adenocarcinoma;

NP_002520

Unknown Primary

Undifferentiated

Neuroendocrine

Carcinoma

1
R104H
LRR 1
0.0500
0.3000
1.0000
0.9180
0.0000
0.0000
Pleura

NM_002529

Mesothelioma

NP_002520

3
V106M
LRR 1
0.1500
0.3000
1.0000
0.8033
0.9958
0.0335
Ovary Serous

A107V

Carcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma;

Unknown Primary

Squamous Cell

Carcinoma

1
A110V
LRR 1
0.0500
0.3000
1.0000
1.0000
0.9427
0.0126
Skin Melanoma

NM_002529

NP_002520

2
H112Y
LRR 1
0.1000
0.3000
1.0000
1.0000
0.9309
0.0250
Bone Marrow

F113L

Multiple Myeloma;

NM_002529

Lung Small Cell

NP_002520

Carcinoma

5
P115S
LRR 2
0.2500
0.3000
0.6000
0.9672
0.7729
0.0168
Lung

R116L

Adenocarcinoma;

R116Q

Colon

R116W

Adenocarcinoma;

L117P

Lung Squamous Cell

NM_002529

Carcinoma

NP_002520

7
R119C
LRR 2
0.3500
0.3000
0.0000
0.8525
0.1038
0.0000
Breast Invasive

R119H

Ductal Carcinoma;

R119P

Lung

NM_002529

Adenocarcinoma;

NP_002520

Colon

Adenocarcinoma

5
A126D
LRR 2
0.2500
0.3000
0.4000
1.0000
0.8130
0.0000
Lung

A126P

Adenocarcinoma;

A126T

Colon

NM_002529

Adenocarcinoma;

NP_002520

Bone Marrow

Multiple Myeloma

1
S129F
LRR 2
0.0500
0.3000
0.0000
1.0000
0.9955
0.0000
Breast Carcinoma

NM_002529

NP_002520

3
W132F
LRR 2
0.1500
0.3000
1.0000
0.9672
0.9902
0.0000
Lung Small Cell

W132R

Undifferentiated

NM_002529

Carcinoma;

NP_002520

Unknown Primary

Malignant

Neoplasm;

Unknown Primary

Squamous Cell

Carcinoma

1
T134N
LRR 2
0.0500
0.3000
1.0000
0.9344
0.9955
0.0000
Pleura

NM_002529

Mesothelioma

NP_002520

3
L138H

0.1500
0.0500
0.3333
1.0000
0.9928
0.0025
Lung

S139F

Adenocarcinoma;

NM_002529

Breast Carcinoma;

NP_002520

Head and Neck

Carcinoma

4
E142K

0.2000
0.0500
1.0000
0.9344
0.9231
0.0000
Breast Invasive

NM_002529

Ductal Carcinoma;

NP_002520

Brain Glioblastoma;

Appendix

Adenocarcinoma

1
G147E

0.0500
0.0500
1.0000
1.0000
0.9350
0.0023
Unknown Primary

NM_002529

Melanoma

NP_002520

4
P149A
LRRCT
0.2000
0.3000
1.0000
0.9016
0.9577
0.0000
Colon

P149H

Adenocarcinoma;

L150P

Stomach

NM_002529

Adenocarcinoma;

NP_002520

Gastroesophageal

Junction

Adenocarcinoma

5
A155V
LRRCT
0.2500
0.3000
0.6000
0.9180
0.1806
0.0000
Colon

L156Q

Adenocarcinoma;

R157C

Pancreas Ductal

R157L

Adenocarcinoma;

R157P

Gastroesophageal

NM_002529

Junction

NP_002520

Adenocarcinoma

5
L156Q
LRRCT
0.2500
0.3000
1.0000
0.9180
0.1924
0.0000
Brain Glioblastoma;

R157C

Pancreas Ductal

R157L

Adenocarcinoma;

R157P

Gastroesophageal

W158R

Junction

NM_002529

Adenocarcinoma

NP_002520

2
R161C
LRRCT
0.1000
0.3000
1.0000
0.9836
0.8626
0.0177
Stomach

R161P

Adenocarcinoma

NM_002529

Intestinal Type;

NP_002520

Placenta

Choriocarcinoma

5
E165D
LRRCT
0.2500
0.3000
0.4000
0.9672
0.7651
0.0136
Colon

E165del

Adenocarcinoma;

G166R

Skin Melanoma;

L167M

Lung Small Cell

NM_002529

Undifferentiated

NP_002520

Carcinoma

7
G169E
LRRCT
0.3500
0.3000
0.0000
0.0000
0.7231
0.0000
Colon

G169R

Adenocarcinoma;

V170L

Head and Neck

P171S

Squamous Cell

P171T

Carcinoma;

NM_002529

Skin Melanoma

NP_002520

1
G179R
LRRCT
0.0500
0.3000
1.0000
1.0000
0.7376
0.0111
Skin Basal Cell

NM_002529

Carcinoma

NP_002520

3
H185N
LRRCT
0.1500
0.3000
1.0000
0.9508
0.8078
0.0115
Breast Carcinoma;

M186T

Lung Non-Small Cell

NM_002529

Lung Carcinoma;

NP_002520

Unknown Primary

Adenocarcinoma

1
A189V
LRRCT
0.0500
0.3000
1.0000
1.0000
0.6980
0.0052
Soft Tissue

NM_002529

Inflammatory

NP_002520

Myofibroblastic

Tumor

1
V193L
LRRCT
0.0500
0.3000
0.0000
1.0000
0.3208
0.0000
Lung

NM_002529

Adenocarcinoma

NP_002520

1
T195M
Ig-like C2-
0.0500
0.9000
1.0000
0.9016
0.0000
0.0000
Lymph Node

NM_002529
type 1

Lymphoma

NP_002520

Plasmablastic

3
K197R
Ig-like C2-
0.1500
0.9000
1.0000
0.9836
0.2979
0.0000
Lung

V198F
type 1

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Melanoma;

Ovary

Carcinosarcoma

14
P201H
Ig-like C2-
0.7000
0.9000
1.0000
0.7869
0.9556
0.0000
Lung

P201del
type 1

Adenocarcinoma;

N202S

Breast Carcinoma;

NM_002529

Brain Glioblastoma

NP_002520

1
D206N
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.3748
0.0169
Skin Melanoma

NM_002529
type 1

NP_002520

2
G208E
Ig-like C2-
0.1000
0.9000
0.0000
1.0000
0.9963
0.0000
Lung

G208R
type 1

Adenocarcinoma;

NM_002529

Brain Glioblastoma

NP_002520

9
D210N
Ig-like C2-
0.4500
0.9000
1.0000
0.9180
0.0000
0.0000
Breast Carcinoma;

V211E
type 1

Bone Marrow

V211L

Multiple Myeloma;

L212V

Skin Melanoma

NM_002529

NP_002520

10
R214Q
Ig-like C2-
0.5000
0.9000
1.0000
0.7377
0.0000
0.0000
Breast Carcinoma;

R214W
type 1

Lung

NM_002529

Adenocarcinoma;

NP_002520

Ovary Serous

Carcinoma

8
R220W
Ig-like C2-
0.4000
0.9000
1.0000
0.9344
0.2129
0.0000
Lung

G221D
type 1

Adenocarcinoma;

G221V

Breast Carcinoma;

L222Q

Breast Invasive

NM_002529

Ductal Carcinoma

NP_002520

6
G221D
Ig-like C2-
0.3000
0.9000
1.0000
1.0000
0.0000
0.0000
Lung

G221V
type 1

Adenocarcinoma;

L222Q

Breast Carcinoma;

E223Q

Breast Invasive

NM_002529

Ductal Carcinoma

NP_002520

3
L222Q
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.0518
0.0023
Lung

E223Q
type 1

Adenocarcinoma

Q224H

NM_002529

NP_002520

3
E223Q
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.0801
0.0108
Lung

Q224H
type 1

Adenocarcinoma;

A225S

Soft Tissue

NM_002529

Neuroblastoma

NP_002520

5
Q224H
Ig-like C2-
0.2500
0.9000
1.0000
0.9672
0.5966
0.0216
Lung

A225S
type 1

Adenocarcinoma;

G226D

Lung Non-Small Cell

G226S

Lung Carcinoma;

NM_002529

Head and Neck

NP_002520

Carcinoma

1
I228V
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.8524
0.0000
Lung

NM_002529
type 1

Adenocarcinoma

NP_002520

1
E231K
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9963
0.0448
Skin Basal Cell

NM_002529
type 1

Carcinoma

NP_002520

2
E233K
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9963
0.0897
Breast Carcinoma;

E233Q
type 1

Lung Squamous Cell

NM_002529

Carcinoma

NP_002520

2
V238M
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9288
0.0836
Head and Neck

M239I
type 1

Squamous Cell

NM_002529

Carcinoma;

NP_002520

Skin Melanoma

3
S241F
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.8094
0.1093
Ovary Serous

S241H
type 1

Carcinoma;

S241Y

Lung Non-Small Cell

NM_002529

Lung Carcinoma

NP_002520

1
G243D
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.0000
0.0000
Breast Carcinoma

NM_002529
type 1

NP_002520

5
P245S
Ig-like C2-
0.2500
0.9000
1.0000
1.0000
0.6902
0.0000
Brain Glioblastoma;

S246F
type 1

Unknown Primary

L247V

Melanoma;

NM_002529

Rectum

NP_002520

Adenocarcinoma

8
S246F
Ig-like C2-
0.4000
0.9000
1.0000
1.0000
0.1783
0.0120
Unknown Primary

L247V
type 1

Melanoma;

G248E

Breast Carcinoma;

G248R

Ovary Serous

NM_002529

Carcinoma

NP_002520

3
L251M
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.9120
0.0205
Breast Invasive

A252S
type 1

Ductal Carcinoma;

N253D

Unknown Primary

NM_002529

Adenocarcinoma;

NP_002520

Lung Small Cell

Undifferentiated

Carcinoma

2
L258I
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9963
0.0673
Lung

L258V
type 1

Adenocarcinoma;

NM_002529

Uterus Endometrial

NP_002520

Adenocarcinoma

5
R260G
Ig-like C2-
0.2500
0.9000
1.0000
0.9836
0.4621
0.0748
Lung

R260M
type 1

Adenocarcinoma;

K261E

Skin Melanoma;

K261N

Uterus Endometrial

N262K

Adenocarcinoma

NM_002529

Endometrioid

NP_002520

4
K261E
Ig-like C2-
0.2000
0.9000
1.0000
0.9344
0.4844
0.0567
Skin Melanoma;

K261N
type 1

Uterus Endometrial

N262K

Adenocarcinoma

V263M

Endometrioid;

NM_002529

Lung Large Cell

NP_002520

Neuroendocrine

Carcinoma

6
N262K
Ig-like C2-
0.3000
0.9000
0.1667
0.9344
0.6661
0.0172
Lung

V263M
type 1

Adenocarcinoma;

T264K

Ovary Serous

T264M

Carcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma

1
W266S
Ig-like C2-
0.0500
0.9000
0.0000
1.0000
0.9963
0.0000
Lung

NM_002529
type 1

Adenocarcinoma

NP_002520

4
D270G
Ig-like C2-
0.2000
0.9000
1.0000
0.9016
0.9504
0.0000
Lung

D270N
type 1

Adenocarcinoma;

NM_002529

Breast Carcinoma;

NP_002520

Skin Melanoma

3
R273Q
Ig-like C2-
0.1500
0.9000
1.0000
0.8197
0.9564
0.0000
Lung

R273W
type 1

Adenocarcinoma;

NM_002529

Bone Marrow

NP_002520

Leukemia

Lymphocytic

Chronic;

Uterus Endometrial

Adenocarcinoma

Papillary Serous

5
E275A
Ig-like C2-
0.2500
0.9000
1.0000
0.6393
0.9893
0.0000
Breast Invasive

NM_002529
type 1

Ductal Carcinoma;

NP_002520

Ovary Serous

Carcinoma;

Soft Tissue Sarcoma

1
S277F
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9974
0.0449
Skin Squamous Cell

NM_002529
type 1

Carcinoma

NP_002520

2
V282I
Ig-like C2-
0.1000
0.9000
0.0000
0.9836
0.9613
0.0000
Lung

NM_002529
type 1

Adenocarcinoma;

NP_002520

Brain Glioblastoma

1
S287I

0.0500
0.0500
1.0000
1.0000
0.9672
0.0012
Cervix

NM_002529

Neuroendocrine

NP_002520

Carcinoma

6
T292M

0.3000
0.0500
1.0000
0.9016
0.3317
0.0000
Lung

A293V

Adenocarcinoma;

V294A

Breast Carcinoma;

NM_002529

Lung Squamous Cell

NP_002520

Carcinoma

3
M296K

0.1500
0.0500
0.0000
1.0000
0.0000
0.0000
Breast Ductal

H297Q

Carcinoma in Situ;

H298Q

Lung Non-Small Cell

NM_002529

Lung Carcinoma;

NP_002520

Lung Large Cell

Neuroendocrine

Carcinoma

2
C300R
Ig-like C2-
0.1000
0.9000
1.0000
0.9672
0.9973
0.0000
Small Intestine

C300Y
type 2

Adenocarcinoma;

NM_002529

Soft Tissue

NP_002520

Myoepithelial

Carcinoma

1
P302L
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9989
0.0000
Breast Invasive

NM_002529
type 2

Ductal Carcinoma

NP_002520

2
S304Y
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9989
0.0804
Lung

NM_002529
type 2

Adenocarcinoma;

NP_002520

Lung Non-Small Cell

Lung Carcinoma

2
D306E
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.0641
0.0058
Pancreas Ductal

G307A
type 2

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Undifferentiated

Small Cell

Carcinoma

4
P309S
Ig-like C2-
0.2000
0.9000
0.0000
1.0000
0.9933
0.0000
Stomach

A310E
type 2

Adenocarcinoma;

A310S

Lung

P311L

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Adenocarcinoma

7
R314G
Ig-like C2-
0.3500
0.9000
1.0000
0.8852
0.9024
0.1258
Lung

R314H
type 2

Adenocarcinoma;

R314L

Head and Neck

R314P

Squamous Cell

NM_002529

Carcinoma;

NP_002520

Bone Marrow

Multiple Myeloma

4
N318S
Ig-like C2-
0.2000
0.9000
1.0000
0.9836
0.9415
0.1550
Head and Neck

G319S
type 2

Squamous Cell

S320F

Carcinoma;

NM_002529

Skin Melanoma;

NP_002520

Ovary Epithelial

Carcinoma

8
G319S
Ig-like C2-
0.4000
0.9000
1.0000
0.9344
0.8913
0.2091
Colon

S320F^1,2,3
type 2

Adenocarcinoma;

V321M^1,2,4

Breast Carcinoma;

NM_002529

Skin Melanoma^1,2,3;

NP_002520

Esophagus and

Stomach

Carcinoma⁴

5
N323S
Ig-like C2-
0.2500
0.9000
0.6000
0.9672
0.9886
0.0362
Breast Invasive

E324D
type 2

Ductal Carcinoma;

E324K

Liver

NM_002529

Cholangiocarcinoma;

NP_002520

Uterus Endometrial

Adenocarcinoma

Endometrioid

2
S326R
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9746
0.0785
Lung

NM_002529
type 2

Adenocarcinoma;

NP_002520

Uterus Endometrial

Adenocarcinoma

10
I328V
Ig-like C2-
0.1500
0.9000
1.0000
0.9836
0.9957
0.0181
Liver Hepatocellular

F329V
type 2

Carcinoma;

T330A

Pancreas Ductal

NM_002529

Adenocarcinoma;

NP_002520

Bladder Urothelial

Carcinoma

6
P335L
Ig-like C2-
0.3000
0.9000
0.0000
0.6885
0.9072
0.0000
Skin Melanoma;

A336E
type 2

Colon

A337P

Adenocarcinoma;

A337T

Breast Carcinoma

NM_002529

NP_002520

14
T340I
Ig-like C2-
0.7000
0.9000
1.0000
0.8361
0.2163
0.0614
Colon

V341M
type 2

Adenocarcinoma;

R342Q

Breast Ductal

R342W

Carcinoma in Situ;

NM_002529

Bone Marrow

NP_002520

Multiple Myeloma

2
G344E
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9862
0.0888
Lung

G344W
type 2

Adenocarcinoma;

NM_002529

Lung

NP_002520

Carcinosarcoma

5
L346P
Ig-like C2-
0.2500
0.9000
0.4000
0.9180
0.9893
0.0434
Colon

R347C
type 2

Adenocarcinoma;

R347G

Uterus Endometrial

R347H

Adenocarcinoma

NM_002529

Endometrioid;

NP_002520

Brain

Medulloblastoma

2
N349K
Ig-like C2-
0.1000
0.9000
1.0000
0.9672
0.9852
0.0000
Breast Invasive

N349S
type 2

Ductal Carcinoma;

NM_002529

Unknown Primary

NP_002520

Malignant Neoplasm

1
G357S
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9989
0.0045
Skin Melanoma

NM_002529
type 2

NP_002520

4
Y359C
Ig-like C2-
0.2000
0.9000
1.0000
0.9672
0.9969
0.0868
Lung

T360M
type 2

Adenocarcinoma;

L361R

Colon

NM_002529

Adenocarcinoma;

NP_002520

Liver

Cholangiocarcinoma

4
P366L

0.2000
0.0500
1.0000
0.9672
0.9818
0.0000
Brain Glioblastoma;

P366R

Unknown Primary

P366S

Adenocarcinoma;

P366T

Unknown Primary

NM_002529

Melanoma

NP_002520

2
G368C

0.1000
0.0500
1.0000
1.0000
0.9985
0.0045
Lung

NM_002529

Adenocarcinoma

NP_002520

5
S371F

0.2500
0.0500
1.0000
0.9672
0.9922
0.0073
Lung Squamous

A372S

Cell Carcinoma;

A372T

Breast Invasive

NM_002529

Lobular Carcinoma;

NP_002520

Soft Tissue

Liposarcoma

7
I374N

0.3500
0.0500
1.0000
0.9508
0.5446
0.0067
Lung

M375I

Adenocarcinoma;

M375V

Brain Glioblastoma;

NM_002529

Lung Squamous Cell

NP_002520

Carcinoma

3
M379T

0.1500
0.0500
1.0000
0.9672
0.9937
0.0000
Unknown Primary

D380G

Melanoma;

N381S

Unknown Primary

NM_002529

Carcinoma;

NP_002520

Small Intestine Gist

3
E388D

0.1500
0.0500
1.0000
1.0000
0.9981
0.0000
Colon

E388K

Adenocarcinoma;

D389Y

Uterus Endometrial

NM_002529

Adenocarcinoma

NP_002520

Endometrioid;

Breast Invasive

Lobular Carcinoma

2
P392S

0.1000
0.0500
1.0000
0.9508
0.9981
0.0000
Bone Marrow

V393F

Multiple Myeloma;

NM_002529

Unknown Primary

NP_002520

Carcinoma

3
F395L

0.1500
0.0500
1.0000
0.9672
0.9980
0.0000
Colon

NM_002529

Adenocarcinoma;

NP_002520

Breast Invasive

Ductal Carcinoma;

Head and Neck

Squamous Cell

Carcinoma

8
P397L

0.4000
0.0500
1.0000
0.8033
0.9980
0.0000
Lung

V398L

Adenocarcinoma;

NM_002529

Ovary Serous

NP_002520

Carcinoma;

Lung Squamous Cell

Carcinoma

3
S402I

0.1500
0.0500
1.0000
1.0000
0.9980
0.0033
Breast Carcinoma;

S402R

Kidney Renal Cell

NM_002529

Carcinoma;

NP_002520

Skin Squamous Cell

Carcinoma

1
S404P

0.0500
0.0500
1.0000
1.0000
0.8904
0.0000
Breast Carcinoma

NM_002529

NP_002520

6
D406Y

0.3000
0.0500
1.0000
0.9344
0.9906
0.0030
Lung

P407L

Adenocarcinoma;

P407R

Colon

V408G

Adenocarcinoma;

NM_002529

Breast Invasive

NP_002520

Ductal Carcinoma

3
K410N

0.1500
0.0500
1.0000
0.9836
0.4940
0.0036
Breast Carcinoma;

K411N

Brain Glioblastoma;

K411del

Unknown Primary

NM_002529

Carcinoma

NP_002520

10
E413K

0.5000
0.0500
0.7000
0.7541
0.9604
0.0039
Colon

E413Q

Adenocarcinoma;

NM_002529

Skin Squamous Cell

NP_002520

Carcinoma;

Breast Invasive

Ductal Carcinoma

3
P415S

0.1500
0.0500
0.0000
1.0000
0.8472
0.0000
Unknown Primary

F416S

Malignant

G417V

Neoplasm;

NM_002529

Lung

NP_002520

Adenocarcinoma

1
S419L

0.0500
0.0500
1.0000
0.9672
0.9972
0.0000
Breast Invasive

NM_002529

Lobular Carcinoma

NP_002520

2
A421T

0.1000
0.0500
1.0000
1.0000
0.9972
0.0047
Lung

V422L

Adenocarcinoma;

NM_002529

Stomach

NP_002520

Adenocarcinoma

Diffuse Type

4
A425S

0.2000
0.0500
1.0000
1.0000
0.9972
0.0000
Ovary Serous

V426I

Carcinoma;

NM_002529

Unknown Primary

NP_002520

Carcinoma;

Uterus Endometrial

Adenocarcinoma

Endometrioid

1
L432R

0.0500
0.0500
1.0000
1.0000
0.9914
0.0012
Breast Invasive

NM_002529

Ductal Carcinoma

NP_002520

4
T434M

0.2000
0.0500
1.0000
0.9672
0.4824
0.0044
Colon

NM_002529

Adenocarcinoma;

NP_002520

Skin Melanoma;

Unknown Primary

Carcinoma

4
N440K

0.2000
0.0500
0.2500
0.7377
0.9375
0.0000
Skin Melanoma;

N440S

Kidney Medullary

NM_002529

Carcinoma;

NP_002520

Soft Tissue

Hemangioendothelioma

6
R444P

0.3000
0.0500
1.0000
0.0000
0.6725
0.0000
Breast Carcinoma;

R444Q

Breast Invasive

R444W

Ductal Carcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma

3
K447M

0.1500
0.0500
1.0000
1.0000
0.9265
0.0010
Colon

K447N

Adenocarcinoma;

K447T

Bladder Urothelial

NM_002529

Carcinoma

NP_002520

14
R452C

0.7000
0.0500
1.0000
0.7377
0.9873
0.0000
Lung

R452G

Adenocarcinoma;

P453L

Lung Squamous Cell

P453Q

Carcinoma;

P453T

Gastroesophageal

A454T

Junction

NM_002529

Adenocarcinoma

NP_002520

6
P453L

0.3000
0.0500
1.0000
0.9180
0.9735
0.0059
Lung Squamous

P453Q

Cell Carcinoma;

P453T

Soft Tissue

A454T

Leiomyosarcoma;

V455M

Adrenal Gland

NM_002529

Neuroblastoma

NP_002520

1
A457V

0.0500
0.0500
1.0000
1.0000
0.9960
0.0025
Unknown Primary

NM_002529

Squamous Cell

NP_002520

Carcinoma

3
D460N

0.1500
0.0500
0.3333
0.9836
0.9960
0.0000
Lung

G461R

Adenocarcinoma;

NM_002529

Skin Melanoma;

NP_002520

Lung Non-Small Cell

Lung Carcinoma

2
S465F

0.1000
0.0500
1.0000
1.0000
0.9949
0.0047
Kidney Renal Cell

S465del

Carcinoma;

NM_002529

Skin Basal Cell

NP_002520

Carcinoma

1
F468L

0.0500
0.0500
1.0000
1.0000
0.9949
0.0002
Unknown Primary

NM_002529

Carcinoma

NP_002520

3
L471F

0.1500
0.0500
1.0000
1.0000
0.4800
0.0027
Lung

G472S

Adenocarcinoma;

NM_002529

Head and Neck

NP_002520

Squamous Cell

Carcinoma;

Lung Sarcomatoid

Carcinoma

8
S475C

0.4000
0.0500
0.6250
0.9672
0.9497
0.0040
Unknown Primary

S475F

Adenocarcinoma;

S475T

Lung

L476M

Adenocarcinoma;

S477Y

Colon

S477_insS

Adenocarcinoma

NM_002529

NP_002520

4
L476M

0.2000
0.0500
0.2500
1.0000
0.9054
0.0014
Lung

S477Y

Adenocarcinoma;

S477_insS

Skin Melanoma;

P478L

Unknown Primary

NM_002529

Adenocarcinoma

NP_002520

4
S477Y

0.2000
0.0500
0.2500
0.9836
0.9794
0.0012
Lung

S477_insS

Adenocarcinoma;

P478L

Brain Glioblastoma;

T479I

Skin Melanoma

NM_002529

NP_002520

4
P478L

0.2000
0.0500
0.2500
0.9672
0.9794
0.0006
Lung

T479I

Adenocarcinoma;

E480K

Brain Glioblastoma;

E480Q

Skin Melanoma

NM_002529

NP_002520

3
S484Y

0.1500
0.0500
1.0000
0.8361
0.9960
0.0000
Lung

G485R

Adenocarcinoma;

L486I

Colon

NM_002529

Adenocarcinoma;

NP_002520

Pancreas Ductal

Adenocarcinoma

3
G485R

0.1500
0.0500
1.0000
0.8361
0.9394
0.0000
Colon

L486I

Adenocarcinoma;

Q487L

Pancreas Ductal

NM_002529

Adenocarcinoma;

NP_002520

Bladder Urothelial

Carcinoma

4
L486I

0.2000
0.0500
1.0000
0.8361
0.9175
0.0047
Colon

Q487L

Adenocarcinoma;

G488C

Lung Squamous Cell

G488S

Carcinoma;

NM_002529

Pancreas Ductal

NP_002520

Adenocarcinoma

5
Q487L

0.2500
0.0500
1.0000
0.9508
0.9204
0.0100
Colon

G488C

Adenocarcinoma;

G488S

Kidney Renal Cell

H489Q

Carcinoma;

H489Y

Lung Squamous Cell

NM_002529

Carcinoma

NP_002520

5
P494T

0.2500
0.0500
1.0000
0.9508
0.9935
0.0000
Ovary Serous

Q495R

Carcinoma;

NM_002529

Pancreas

NP_002520

Carcinoma;

Soft Tissue Ewing

Sarcoma

1
A500T

0.0500
0.0500
1.0000
1.0000
0.9324
0.0021
Lymph Node

NM_002529

Lymphoma Follicular

NP_002520

Lymphoma

4
V502A

0.2000
0.0500
0.2500
1.0000
0.9950
0.0019
Breast Carcinoma;

H503N

Skin Melanoma;

H503Y

Bile Duct

NM_002529

Adenocarcinoma

NP_002520

10
R507C

0.5000
0.0500
1.0000
0.5902
0.8988
0.0108
Bladder Urothelial

R507H

Carcinoma;

R508Q

Lung

R508W

Adenocarcinoma;

NM_002529

Breast Invasive

NP_002520

Ductal Carcinoma

4
I510T
Protein
0.2000
1.0000
1.0000
0.8525
0.9837
0.1606
Unknown Primary

V511M
kinase

Adenocarcinoma;

L512F

Unknown Primary

L512R

Melanoma;

NM_002529

Uterus Endometrial

NP_002520

Adenocarcinoma

Endometrioid

1
E515K
Protein
0.0500
1.0000
1.0000
1.0000
0.9976
0.0050
Unknown Primary

NM_002529
kinase

Melanoma

NP_002520

2
G517R
Protein
0.1000
1.0000
0.0000
1.0000
0.9976
0.0000
Skin Melanoma;

E518K
kinase

Rectum

NM_002529

Adenocarcinoma

NP_002520

1
A520T
Protein
0.0500
1.0000
1.0000
1.0000
0.9976
0.0499
Uterus Endometrial

NM_002529
kinase

Adenocarcinoma

NP_002520

1
G522W
Protein
0.0500
1.0000
1.0000
1.0000
0.9976
0.0249
Eye Lacrimal Duct

NM_002529
kinase

Carcinoma

NP_002520

4
L526F
Protein
0.2000
1.0000
0.2500
1.0000
0.9749
0.0081
Lung

L526P
kinase

Adenocarcinoma;

A527T

Colon

NM_002529

Adenocarcinoma;

NP_002520

Unknown Primary

Melanoma

1
H530Y
Protein
0.0500
1.0000
1.0000
1.0000
0.7968
0.0356
Esophagus

NM_002529
kinase

Adenocarcinoma

NP_002520

1
L533Q
Protein
0.0500
1.0000
1.0000
1.0000
0.9923
0.0496
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

2
D537E
Protein
0.1000
1.0000
1.0000
1.0000
0.9767
0.0874
Colon

D537N
kinase

Adenocarcinoma;

NM_002529

Ovary Serous

NP_002520

Carcinoma

4
M539L
Protein
0.2000
1.0000
1.0000
1.0000
0.9663
0.0000
Lung

M539R
kinase

Adenocarcinoma;

L540Q

Breast Invasive

V541M

Ductal Carcinoma

NM_002529

NP_002520

1
V543A
Protein
0.0500
1.0000
1.0000
1.0000
0.9923
0.0050
Uterus

NM_002529
kinase

Leiomyosarcoma

NP_002520

1
K547T
Protein
0.0500
1.0000
1.0000
1.0000
0.9939
0.0445
Head and Neck

NM_002529
kinase

Squamous Cell

NP_002520

Carcinoma

5
A549T
Protein
0.2500
1.0000
0.0000
0.8689
0.6778
0.0000
Lung

A549V
kinase

Adenocarcinoma;

S550Y

Colon

E551D

Adenocarcinoma;

E551V

Breast Invasive

NM_002529

Ductal Carcinoma

NP_002520

4
S550Y
Protein
0.2000
1.0000
0.0000
1.0000
0.9961
0.0000
Lung

E551D
kinase

Adenocarcinoma;

E551V

Lung Non-Small Cell

S552R

Lung Carcinoma

NM_002529

NP_002520

4
E551D
Protein
0.2000
1.0000
0.2500
1.0000
0.9961
0.0427
Lung

E551V
kinase

Adenocarcinoma;

S552R

Lung Non-Small Cell

A553T

Lung Carcinoma;

NM_002529

Unknown Primary

NP_002520

Adenocarcinoma

6
S552R
Protein
0.3000
1.0000
1.0000
0.8852
0.8492
0.1121
Lung

A553T
kinase

Adenocarcinoma;

R554P

Unknown Primary

R554Q

Adenocarcinoma;

R554W

Pleura

NM_002529

Mesothelioma

NP_002520

1
D556N
Protein
0.0500
1.0000
1.0000
1.0000
0.9982
0.0499
Unknown Primary

NM_002529
kinase

Melanoma

NP_002520

2
R559H
Protein
0.1000
1.0000
0.0000
0.9508
0.9982
0.0000
Lung

NM_002529
kinase

Adenocarcinoma;

NP_002520

Colon

Adenocarcinoma

1
A561T
Protein
0.0500
1.0000
0.0000
1.0000
0.9982
0.0000
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

1
M566K
Protein
0.0500
1.0000
1.0000
0.9836
0.9939
0.0000
Colon

NM_002529
kinase

Adenocarcinoma

NP_002520

1
Q570R
Protein
0.0500
1.0000
1.0000
1.0000
0.9939
0.0050
Bone Marrow

NM_002529
kinase

Leukemia Non-

NP_002520

Lymph ocytic Acute

Myelocytic

8
V573M
Protein
0.4000
1.0000
0.1250
0.9016
0.9977
0.0000
Lung Non-Small Cell

R574C
kinase

Lung Carcinoma;

R574H

Breast Carcinoma;

F575L

Ovary Serous

NM_002529

Carcinoma

NP_002520

3
G577S
Protein
0.1500
1.0000
0.0000
0.9180
0.9982
0.0000
Colon

V578I
kinase

Adenocarcinoma;

NM_002529

Brain Glioblastoma;

NP_002520

Lung Non-Small Cell

Lung Carcinoma

1
T580I
Protein
0.0500
1.0000
0.0000
1.0000
0.9982
0.0000
Lung Large Cell

NM_002529
kinase

Neuroendocrine

NP_002520

Carcinoma

6
R583C
Protein
0.3000
1.0000
1.0000
0.8689
0.9679
0.0000
Lung Squamous

R583L
kinase

Cell Carcinoma;

NM_002529

Ovary Serous

NP_002520

Carcinoma;

Head and Neck

Squamous Cell

Carcinoma

1
L585R
Protein
0.0500
1.0000
1.0000
1.0000
0.9939
0.0000
Ovary Serous

NM_002529
kinase

Carcinoma

NP_002520

1
M587T
Protein
0.0500
1.0000
1.0000
1.0000
0.9939
0.0497
Breast Carcinoma

NM_002529
kinase

NP_002520

1
Y591C
Protein
0.0500
1.0000
1.0000
1.0000
0.9939
0.0497
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

7
R593W
Protein
0.3500
1.0000
0.5714
0.7541
0.7196
0.0649
Colon

H594Q
kinase

Adenocarcinoma;

G595R

Lung

NM_002529

Adenocarcinoma;

NP_002520

Breast Invasive

Ductal Carcinoma

5
R599H
Protein
0.2500
1.0000
1.0000
0.9508
0.9982
0.0000
Lung

NM_002529
kinase

Adenocarcinoma;

NP_002520

Breast Invasive

Ductal Carcinoma;

Unknown Primary

Adenocarcinoma

3
R602Q
Protein
0.1500
1.0000
0.0000
1.0000
0.9952
0.0000
Lung

S603P
kinase

Adenocarcinoma;

NM_002529

Head and Neck

NP_002520

Squamous Cell

Carcinoma;

Bone Marrow

Multiple Myeloma

2
P606H
Protein
0.1000
1.0000
1.0000
1.0000
0.9963
0.0926
Uterus Endometrial

D607N
kinase

Adenocarcinoma

NM_002529

Endometrioid;

NP_002520

Lung Sarcomatoid

Carcinoma

1
K609N
Protein
0.0500
1.0000
0.0000
1.0000
0.9316
0.0000
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

2
A612S
Protein
0.1000
1.0000
1.0000
1.0000
0.9963
0.0000
Prostate Acinar

A612V
kinase

Adenocarcinoma;

NM_002529

Breast Adenoid

NP_002520

Cystic Carcinoma

6
G614A
Protein
0.3000
1.0000
0.5000
1.0000
0.9763
0.0262
Lung

G614V
kinase

Adenocarcinoma;

E615K

Brain Glioblastoma;

E615Q

Skin Melanoma

D616H

D616N

NM_002529

NP_002520

1
A618V
Protein
0.0500
1.0000
1.0000
1.0000
0.9963
0.0000
Nasopharynx and

NM_002529
kinase

Paranasal Sinuses

NP_002520

Undifferentiated

Carcinoma

1
G620C
Protein
0.0500
1.0000
0.0000
1.0000
0.9963
0.0000
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

2
G623C
Protein
0.1000
1.0000
1.0000
0.9672
0.7246
0.0000
Breast Carcinoma;

NM_002529
kinase

Skin Squamous Cell

NP_002520

Carcinoma

1
Q626K
Protein
0.0500
1.0000
1.0000
1.0000
0.9963
0.0446
Breast Ductal

NM_002529
kinase

Carcinoma in Situ

NP_002520

2
V630A
Protein
0.1000
1.0000
1.0000
1.0000
0.9928
0.0000
Bladder Urothelial

A631D
kinase

Carcinoma;

NM_002529

Unknown Primary

NP_002520

Melanoma

7
A636E
Protein
0.3500
1.0000
0.5714
0.9672
0.9953
0.1363
Colon

A636T
kinase

Adenocarcinoma;

A636V

Skin Melanoma;

G637E

Lung Small Cell

G637W

Undifferentiated

M638V

Carcinoma

NM_002529

NP_002520

6
G637E
Protein
0.3000
1.0000
1.0000
0.9672
0.9951
0.0578
Ovary Serous

G637W
kinase

Carcinoma;

M638V

Skin Squamous Cell

V639L

Carcinoma;

V639M

Bile Duct

NM_002529

Adenocarcinoma

NP_002520

6
M638V
Protein
0.3000
1.0000
1.0000
0.9672
0.9916
0.0000
Lung

V639L
kinase

Adenocarcinoma;

V639M

Ovary Serous

Y640C

Carcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma

6
V639L
Protein
0.3000
1.0000
1.0000
0.9836
0.9821
0.0000
Lung

V639M
kinase

Adenocarcinoma;

Y640C

Ovary Serous

L641M

Carcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma

6
Y640C
Protein
0.3000
1.0000
0.0000
0.9836
0.9821
0.0000
Lung

L641M
kinase

Adenocarcinoma;

A642S

Colon

A642V

Adenocarcinoma;

NM_002529

Lung Non-Small Cell

NP_002520

Lung Carcinoma

1
L644M
Protein
0.0500
1.0000
0.0000
1.0000
0.7447
0.0000
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

7
V647G
Protein
0.3500
1.0000
0.7143
0.8525
0.9733
0.0000
Lung

V647L
kinase

Adenocarcinoma;

NM_002529

Colon

NP_002520

Adenocarcinoma;

Head and Neck

Squamous Cell

Carcinoma

6
R649L
Protein
0.3000
1.0000
0.5000
1.0000
0.9446
0.1267
Lung

R649W
kinase

Adenocarcinoma;

NM_002529

Colon

NP_002520

Adenocarcinoma;

Ovary Serous

Carcinoma

1
L651M
Protein
0.0500
1.0000
0.0000
1.0000
0.9359
0.0000
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

6
R654C
Protein
0.3000
1.0000
0.5000
0.9180
0.9951
0.1246
Lung

R654H
kinase

Adenocarcinoma;

N655Y

Breast Carcinoma;

NM_002529

Colon

NP_002520

Adenocarcinoma

2
L657P
Protein
0.1000
1.0000
1.0000
1.0000
0.8658
0.0000
Colon

L657V
kinase

Adenocarcinoma;

NM_002529

Pleura

NP_002520

Mesothelioma

2
Q660L
Protein
0.1000
1.0000
0.0000
1.0000
0.9922
0.0000
Skin Melanoma

G661E
kinase

NM_002529

NP_002520

2
V663E
Protein
0.1000
1.0000
0.0000
1.0000
0.9909
0.0000
Lung

V664I
kinase

Adenocarcinoma

NM_002529

Skin Melanoma

NP_002520

1
I666T
Protein
0.0500
1.0000
0.0000
1.0000
0.9867
0.0000
Lung Non-Small Cell

NM_002529
kinase

Lung Carcinoma

NP_002520

1
M671T
Protein
0.0500
1.0000
1.0000
1.0000
0.9867
0.0441
Colon

NM_002529
kinase

Adenocarcinoma

NP_002520

2
D674E
Protein
0.1000
1.0000
0.0000
1.0000
0.2552
0.0000
Lung

D674N
kinase

Adenocarcinoma;

NM_002529

Skin Merkel Cell

NP_002520

Carcinoma

1
S677N
Protein
0.0500
1.0000
1.0000
1.0000
0.9952
0.0050
Uterus Endometrial

NM_002529
kinase

Adenocarcinoma

NP_002520

Papillary Serous

5
D679N^1,2,5
Protein
0.2500
1.0000
1.0000
0.9508
0.9935
0.2137
Lung Small Cell

D679Y
kinase

Undifferentiated

Y680H

Carcinoma;

NM_002529

Prostate Acinar

NP_002520

Adenocarcinoma;

Uterus Endometrial

Adenocarcinoma

Endometrioid;

Uterine Corpus

Endometrioid

Carcinoma^1,2,5

9
R682C
Protein
0.4500
1.0000
0.3333
0.0000
0.9932
0.0000
Colon

R682H
kinase

Adenocarcinoma;

R682S

Lung

V683G

Adenocarcinoma;

G684E

Lung Squamous Cell

NM_002529

Carcinoma

NP_002520

8
R686G
Protein
0.4000
1.0000
0.2500
0.9672
0.9957
0.0401
Lung

R686H
kinase

Adenocarcinoma;

T687I

Colon

M688I

Adenocarcinoma;

NM_002529

Skin Melanoma

NP_002520

3
T687I
Protein
0.1500
1.0000
1.0000
1.0000
0.9957
0.1493
Skin Melanoma;

M688I
kinase

Unknown Primary

L689M

Melanoma;

NM_002529

Uterus Endometrial

NP_002520

Adenocarcinoma

Papillary Serous

3
M688I
Protein
0.1500
1.0000
1.0000
1.0000
0.9957
0.1493
Unknown Primary

L689M
kinase

Melanoma;

P690H

Lung Small Cell

NM_002529

Undifferentiated

NP_002520

Carcinoma;

Uterus Endometrial

Adenocarcinoma

Papillary Serous

6
R692C
Protein
0.3000
1.0000
0.5000
0.9180
0.9957
0.1240
Colon

R692H
kinase

Adenocarcinoma;

NM_002529

Skin Melanoma;

NP_002520

Unknown Primary

Adenocarcinoma

4
P695S
Protein
0.2000
1.0000
1.0000
0.9836
0.9957
0.1778
Skin Melanoma;

P696L
kinase

Prostate Acinar

E697K

Adenocarcinoma;

NM_002529

Uterus Endometrial

NP_002520

Adenocarcinoma

Endometrioid

1
I699V
Protein
0.0500
1.0000
1.0000
1.0000
0.9878
0.0442
Colon

NM_002529
kinase

Adenocarcinoma

NP_002520

12
R702C
Protein
0.6000
1.0000
0.1667
0.8361
0.9957
0.0423
Lung

R702H
kinase

Adenocarcinoma;

R702L

Ovary Serous

R702S

Carcinoma;

NM_002529

Skin Melanoma

NP_002520

2
T705S
Protein
0.1000
1.0000
1.0000
0.0000
0.9917
0.0000
Breast Carcinoma;

T706K
kinase

Unknown Primary

NM_002529

Adenocarcinoma

NP_002520

5
D709N
Protein
0.2500
1.0000
0.0000
0.9508
0.9957
0.0000
Lung

D709Y
kinase

Adenocarcinoma;

V710M

Skin Melanoma;

NM_002529

Unknown Primary

NP_002520

Melanoma

1
S712R
Protein
0.0500
1.0000
0.0000
1.0000
0.9957
0.0000
Colon

NM_002529
kinase

Adenocarcinoma

NP_002520

3
V715M
Protein
0.1500
1.0000
1.0000
0.9836
0.9957
0.0000
Colon

NM_002529
kinase

Adenocarcinoma;

NP_002520

Breast Invasive

Ductal Carcinoma;

Uterus Endometrial

Adenocarcinoma

3
E719D
Protein
0.1500
1.0000
0.3333
1.0000
0.9950
0.0415
Colon

E719K
kinase

Adenocarcinoma;

NM_002529

Breast Invasive

NP_002520

Ductal Carcinoma;

Unknown Primary

Melanoma

1
Y723C
Protein
0.0500
1.0000
1.0000
1.0000
0.9857
0.0493
Leukemia

NM_002529
kinase

Lymphocytic Chronic

NP_002520

2
K725M
Protein
0.1000
1.0000
1.0000
1.0000
0.9857
0.0099
Lung

K725T
kinase

Adenocarcinoma;

NM_002529

Breast Carcinoma

NP_002520

1
W728R
Protein
0.0500
1.0000
1.0000
1.0000
0.9857
0.0493
Lung

NM_002529
kinase

Adenocarcinoma

NP_002520

2
N733S
Protein
0.1000
1.0000
1.0000
0.9016
0.9902
0.0000
Stomach

T734M
kinase

Adenocarcinoma;

NM_002529

Unknown Primary

NP_002520

Melanoma

2
A736E
Protein
0.1000
1.0000
1.0000
1.0000
0.9744
0.0487
Lung

A736T
kinase

Adenocarcinoma;

NM_002529

Uterus Endometrial

NP_002520

Adenocarcinoma

Papillary Serous

11
T741M
Protein
0.5500
1.0000
1.0000
0.9016
0.9975
0.0000
Lung

NM_002529
kinase

Adenocarcinoma;

NP_002520

Colon

Adenocarcinoma;

Kidney Renal Cell

Carcinoma

9
G743R
Protein
0.4500
1.0000
1.0000
0.6066
0.9574
0.0000
Lung

R744C
kinase

Adenocarcinoma;

R744H

Breast Carcinoma;

NM_002529

Skin Melanoma

NP_002520

7
E747K
Protein
0.3500
1.0000
1.0000
0.9344
0.9837
0.1707
Lung

R748L
kinase

Adenocarcinoma;

R748Q

Lung Non-Small Cell

R748W

Lung Carcinoma;

P749Q

Liver Hepatocellular

NM_002529

Carcinoma

NP_002520

11
R748L
Protein
0.5500
1.0000
0.5455
0.9180
0.9887
0.1753
Lung

R748Q
kinase

Adenocarcinoma;

R748W

Breast Carcinoma;

P749Q

Lung Non-Small Cell

R750C

Lung Carcinoma

R750H

R750L

NM_002529

NP_002520

7
P749Q
Protein
0.3500
1.0000
0.2857
0.9836
0.9975
0.0701
Lung

R750C
kinase

Adenocarcinoma;

R750H

Breast Carcinoma;

R750L

Head and Neck

A751D

Squamous Cell

NM_002529

Carcinoma

NP_002520

3
P753Q
Protein
0.1500
1.0000
0.0000
1.0000
0.9975
0.0000
Lung

P754T
kinase

Adenocarcinoma;

E755Q

Breast Carcinoma;

NM_002529

Unknown Primary

NP_002520

Carcinoma

9
M760I
Protein
0.4500
1.0000
1.0000
0.5574
0.9763
0.0000
Breast Carcinoma;

M760V
kinase

Lung

R761Q

Adenocarcinoma;

R761W

Colon

G762R

Adenocarcinoma

NM_002529

NP_002520

8
R761Q
Protein
0.4000
1.0000
1.0000
0.5574
0.9744
0.0000
Lung

R761W
kinase

Adenocarcinoma;

G762R

Colon

C763F

Adenocarcinoma;

NM_002529

Breast Carcinoma

NP_002520

2
R766L
Protein
0.1000
1.0000
1.0000
0.9344
0.9744
0.0910
Lung

R766W
kinase

Adenocarcinoma

NM_002529

NP_002520

1
P768S
Protein
0.0500
1.0000
1.0000
1.0000
0.9975
0.0446
Uterus Endometrial

NM_002529
kinase

Adenocarcinoma

NP_002520

Papillary Serous

5
R771H
Protein
0.2500
1.0000
1.0000
0.9508
0.7407
0.0000
Lung

H772R
kinase

Adenocarcinoma;

NM_002529

Pancreas Ductal

NP_002520

Adenocarcinoma;

Unknown Primary

Adenocarcinoma

4
D776E
Protein
0.2000
1.0000
1.0000
1.0000
0.4962
0.0136
Lung

D776N
kinase

Adenocarcinoma;

V777A

Colon

NM_002529

Adenocarcinoma;

NP_002520

Lung Non-Small Cell

Lung Carcinoma

8
A779T
Protein
0.4000
1.0000
1.0000
0.9344
0.6010
0.0000
Colon

R780G
kinase

Adenocarcinoma;

R780W

Ovary Serous

NM_002529

Carcinoma;

NP_002520

Unknown Primary

Adenocarcinoma

4
P788L

0.2000
0.0500
1.0000
0.9836
0.9659
0.0000
Colon

P788S

Adenocarcinoma;

NM_002529

Breast Carcinoma;

NP_002520

Unknown Primary

Adenocarcinoma

4
V790I

0.2000
0.0500
1.0000
0.9180
0.9461
0.0000
Lung

V790L

Adenocarcinoma;

Y791H

Ovary Serous

NM_002529

Carcinoma;

NP_002520

Kidney Renal Cell

Carcinoma

¹Ovarian Cancer Gene Database, ocgene.bioinfo-minzhao.org/gene_mutation.cgi?gene=4914, downloaded on May 31, 2016.

²Pediatric Cancer Gene Database, pedican.bioinfo-minzhao org/gene_mutation.cgi?gene=4914, downloaded on May 31, 2016.

³Catalog of Somatic Mutations in Cancer (COSMIC) database, cancer.sanger.ac.uk/cosmic/mutation/overview?id=1688778, downloaded on May 31, 2016.

⁴Catalog of Somatic Mutations in Cancer (COSMIC) database, cancer.sanger.ac.uk/cosmic/mutation/overview?id=1259646, downloaded on May 31, 2016.

⁵Catalog of Somatic Mutations in Cancer (COSMIC) database, cancer.sanger.ac.uk/cosmic/mutation/overview?id=897427, downloaded on May 31, 2016.

TABLE 2

Detected TrkB Protein Mutations Resulting from NTRK2 Point Mutations Detected in Cancer Biopsy Samples

Mutated
Mutations

Hotspot
Domain
co-Alteration
Exac
Conservation
Total

Samples
Ref. Transcript/Protein
Domain
Score
Score
Score
Score
Score
Score
Disease

1
W7R

0.0500
0.0500
0.0000
1.0000
0.9920
0.0000
Breast Carcinoma

NM_006180

NP_006171

3
G9E

0.1500
0.0500
1.0000
1.0000
0.9828
0.0010
Lung Adenocarcinoma;

G9V

Soft Tissue

P10H

Inflammatory

NM_006180

Myofibroblastic Tumor

NP_006171

1
R14W

0.0500
0.0500
1.0000
1.0000
0.9975
0.0025
Skin Squamous Cell

NM_006180

Carcinoma

NP_006171

2
V23A

0.1000
0.0500
1.0000
0.9836
0.0000
0.0000
Lung Non-Small Cell

V23M

Lung Carcinoma;

NM_006180

Unknown Primary

NP_006171

Undifferentiated

Neuroendocrine

Carcinoma

1
W26R

0.0500
0.0500
1.0000
0.9836
0.9920
0.0024
Lung Adenocarcinoma

NM_006180

NP_006171

3
A28D

0.1500
0.0500
0.0000
1.0000
0.9628
0.0000
Lung Adenocarcinoma;

A29T

Gastroesophageal

NM_006180

Junction

NP_006171

Adenocarcinoma

1
A31T

0.0500
0.0500
1.0000
0.9836
0.9511
0.0000
Lung Adenosquamous

NM_006180

Carcinoma

NP_006171

3
T34A
LRRNT
0.1500
0.3000
0.3333
0.8525
0.5091
0.0000
Breast Invasive Ductal

T34R

Carcinoma;

S35F

Kidney Renal Cell

NM_006180

Carcinoma;

NP_006171

Skin Melanoma

1
K37R
LRRNT
0.0500
0.3000
1.0000
1.0000
0.0667
0.0000
Bone Marrow

NM_006180

Leukemia Non-

NP_006171

Lymphocytic Acute

Myelocytic

1
R42Q
LRRNT
0.0500
0.3000
0.0000
1.0000
0.9975
0.0000
Lung Adenocarcinoma

NM_006180

NP_006171

5
C45F
LRRNT
0.2500
0.3000
1.0000
0.9836
0.9333
0.0510
Lung Adenocarcinoma;

C45R

Head and Neck

C45Y

Squamous Cell

S46R

Carcinoma;

D47N

Uterus Endometrial

NM_006180

Adenocarcinoma

NP_006171

Endometrioid

1
G51D
LRRNT
0.0500
0.3000
1.0000
1.0000
0.9975
0.0150
Skin Melanoma

NM_006180

NP_006171

1
V53A
LRRNT
0.0500
0.3000
1.0000
1.0000
0.9920
0.0015
Unknown Primary

NM_006180

Squamous Cell

NP_006171

Carcinoma

5
P56L
LRRNT
0.2500
0.3000
0.0000
1.0000
0.8209
0.0000
Breast Ductal

P56S

Carcinoma in Situ;

R57S

Brain Glioblastoma;

NM_006180

Unknown Primary

NP_006171

Carcinoma

1
P60H
LRRNT
0.0500
0.3000
1.0000
0.9836
0.9522
0.0000
Lung Adenocarcinoma

NM_006180

NP_006171

3
P65H

0.1500
0.0500
1.0000
1.0000
0.8478
0.0028
Thyroid Papillary

P65T

Carcinoma;

E66D

Stomach

NM_006180

Adenocarcinoma

NP_006171

Diffuse Type;

Eye Intraocular

Melanoma

3
T69P

0.1500
0.0500
1.0000
1.0000
0.9957
0.0025
Kidney Urothelial

T69S

Carcinoma;

E70K

Uterus

NM_006180

Carcinosarcoma;

NP_006171

Bone Sarcoma

1
F72L

0.0500
0.0500
1.0000
1.0000
0.8906
0.0022
Colon Adenocarcinoma

NM_006180

NP_006171

2
A74S

0.1000
0.0500
0.0000
1.0000
0.5829
0.0000
Lung Non-Small Cell

N75K

Lung Carcinoma;

NM_006180

Soft Tissue Ewing

NP_006171

Sarcoma

1
R78K

0.0500
0.0500
1.0000
1.0000
0.9533
0.0012
Brain

NM_006180

Oligodendroglioma

NP_006171

3
E80Q

0.1500
0.0500
1.0000
1.0000
0.9575
0.0000
Colon

I81F

Adenocarcinoma;

I82V

Lung Squamous Cell

NM_006180

Carcinoma;

NP_006171

Lung Atypical

Carcinoid

1
E84K

0.0500
0.0500
1.0000
1.0000
0.9976
0.0012
Head and Neck

NM_006180

Squamous Cell

NP_006171

Carcinoma

5
E88K

0.2500
0.0500
1.0000
1.0000
0.9976
0.0115
Lung Adenocarcinoma;

E88Q

Lung Non-Small Cell

A89T

Lung Carcinoma;

NM_006180

Unknown Primary

NP_006171

Melanoma

2
T97A
LRR1
0.1000
0.3000
1.0000
1.0000
0.9924
0.0000
Lung Adenocarcinoma;

I98V

Ovary Granulosa Cell

NM_006180

Tumor

NP_006171

2
D100N
LRR1
0.1000
0.3000
1.0000
1.0000
0.9981
0.0299
Unknown Primary

S101F

Malignant Neoplasm;

NM_006180

Duodenum

NP_006171

Adenocarcinoma

1
F105L
LRR1
0.0500
0.3000
1.0000
1.0000
0.9935
0.0133
Skin Squamous Cell

NM_006180

Carcinoma

NP_006171

1
A110E
LRR1
0.0500
0.3000
1.0000
1.0000
0.9981
0.0150
Lung Adenocarcinoma

NM_006180

NP_006171

1
K113R
LRR1
0.0500
0.3000
1.0000
1.0000
0.8998
0.0135
Ovary Serous

NM_006180

Carcinoma

NP_006171

2
I120N
LRR2
0.1000
0.3000
1.0000
0.9836
0.9481
0.0210
Pancreas Ductal

I120V

Adenocarcinoma;

NM_006180

Unknown Primary

NP_006171

Adenocarcinoma

1
F122I
LRR2
0.0500
0.3000
1.0000
0.9836
0.9049
0.0000
Colon Carcinoid Tumor

NM_006180

NP_006171

2
R124Q
LRR2
0.1000
0.3000
1.0000
0.8525
0.5752
0.0000
Ovary Serous

N125K

Carcinoma;

NM_006180

Lung Squamous Cell

NP_006171

Carcinoma

2
R132S
LRR2
0.1000
0.3000
0.0000
1.0000
0.3113
0.0000
Lung Non-Small Cell

K133N

Lung Carcinoma;

NM_006180

Lymph Node

NP_006171

Lymphoma Diffuse

Large B Cell

2
R136C
LRR2
0.1000
0.3000
1.0000
0.8689
0.9066
0.0211
Colon

R136H

Adenocarcinoma;

NM_006180

Breast Ductal

NP_006171

Carcinoma in Situ

2
L138F

0.1000
0.0500
1.0000
1.0000
0.9977
0.0045
Lung Adenocarcinoma;

D139H

Thymus Carcinoma

NM_006180

NP_006171

5
V146A

0.2500
0.0500
0.4000
1.0000
0.7006
0.0000
Lung Adenocarcinoma;

V146L

Colon

G147S

Adenocarcinoma;

NM_006180

Lung Small Cell

NP_006171

Undifferentiated

Carcinoma

3
W158C
LRRCT
0.1500
0.3000
0.0000
1.0000
0.8642
0.0000
Lung Adenocarcinoma;

I159F

Liver Hepatocellular

I159M

Carcinoma;

NM_006180

Gastroesophageal

NP_006171

Junction

Adenocarcinoma

1
K166T
LRRCT
0.0500
0.3000
1.0000
0.9836
0.9938
0.0000
Breast Invasive Ductal

NM_006180

Carcinoma

NP_006171

1
P169S
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9612
0.0072
Soft Tissue

NM_006180

Inflammatory

NP_006171

Myofibroblastic Tumor

2
Q172K
LRRCT
0.1000
0.3000
0.0000
1.0000
0.9650
0.0000
Lung Adenocarcinoma

D173Y

NM_006180

NP_006171

1
Y175H
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9938
0.0133
Lung Small Cell

NM_006180

Carcinoma

NP_006171

1
P185L
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9982
0.0150
Skin Squamous Cell

NM_006180

Carcinoma

NP_006171

3
A187E
LRRCT
0.1500
0.3000
1.0000
0.8197
0.9226
0.0000
Head and Neck

A187S

Squamous Cell

NM_006180

Carcinoma;

NP_006171

Stomach

Adenocarcinoma;

Uterus Endometrial

Adenocarcinoma

Endometrioid

1
I191T
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9938
0.0015
Breast Carcinoma

NM_006180

NP_006171

1
N193S
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9938
0.0015
Uterus Endometrial

NM_006180

Adenocarcinoma

NP_006171

2
G195A
LRRCT
0.1000
0.3000
1.0000
1.0000
0.9297
0.0000
Lung Small Cell

L196F

Undifferentiated

NM_006180

Carcinoma;

NP_006171

Unknown Primary

Malignant Neoplasm

3
S198T
Ig-likeC2-
0.1500
0.9000
0.0000
1.0000
0.9971
0.0000
Lung Adenocarcinoma;

A199T
type1

Bone Marrow

NM_006180

Leukemia Lymphocytic

NP_006171

Chronic;

Leukemia Lymphocytic

Chronic

3
A202D
Ig-likeC2-
0.1500
0.9000
1.0000
0.9344
0.9888
0.0000
Lung Adenocarcinoma;

A203S
type1

Unknown Primary

NM_006180

Carcinoma;

NP_006171

Anus Squamous Cell

Carcinoma

1
T207I
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9983
0.0402
Skin Melanoma

NM_006180
type1

NP_006171

5
E209D
Ig-likeC2-
0.2500
0.9000
0.4000
1.0000
0.9395
0.0743
Lung Adenocarcinoma;

E209K
type1

Skin Melanoma;

E210V

Unknown Primary

NM_006180

Adenocarcinoma

NP_006171

4
A221V
Ig-likeC2-
0.2000
0.9000
1.0000
1.0000
0.9741
0.0000
Lung Small Cell

G222D
type1

Undifferentiated

D223H

Carcinoma;

NM_006180

Uterus Endometrial

NP_006171

Adenocarcinoma

Endometrioid;

Duodenum

Adenocarcinoma

4
G222D
Ig-likeC2-
0.2000
0.9000
1.0000
1.0000
0.9828
0.0000
Lung Small Cell

D223H
type1

Undifferentiated

P224S

Carcinoma;

NM_006180

Uterus Endometrial

NP_006171

Adenocarcinoma

Endometrioid;

Fallopian Tube Serous

Carcinoma

4
D223H
Ig-likeC2-
0.2000
0.9000
1.0000
1.0000
0.9417
0.0000
Lung Small Cell

P224S
type1

Undifferentiated

V225I

Carcinoma;

NM_006180

Kidney Renal Cell

NP_006171

Carcinoma;

Fallopian Tube Serous

Carcinoma

1
M228T
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9942
0.0447
Liver Hepatocellular

NM_006180
type1

Carcinoma

NP_006171

1
W230L
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9984
0.0449
Breast Metaplastic

NM_006180
type1

Carcinoma

NP_006171

1
N234Y
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9946
0.0400
Bladder Urothelial

NM_006180
type1

Carcinoma

NP_006171

5
M240I
Ig-likeC2-
0.2500
0.9000
0.4000
1.0000
0.9968
0.0425
Skin Melanoma;

N241D
type1

Unknown Primary

E242K

Adenocarcinoma;

NM_006180

Unknown Primary

NP_006171

Melanoma

4
S249F
Ig-likeC2-
0.2000
0.9000
1.0000
0.9016
0.7991
0.0000
Unknown Primary

S249Y
type1

Melanoma;

NM_006180

Soft Tissue

NP_006171

Leiomyosarcoma;

Ovary Carcinosarcoma

3
R251G
Ig-likeC2-
0.1500
0.9000
1.0000
1.0000
0.9427
0.1273
Breast Invasive Ductal

R251K
type1

Carcinoma;

I252V

Lung Non-Small Cell

NM_006180

Lung Carcinoma;

NP_006171

Gastroesophageal

Junction

Adenocarcinoma

1
N254S
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9925
0.0400
Colon Adenocarcinoma

NM_006180
type1

NP_006171

4
S256L
Ig-likeC2-
0.2000
0.9000
1.0000
1.0000
0.9976
0.1520
Lung Adenocarcinoma;

S257F
type1

Soft Tissue Sarcoma;

D258N

Unknown Primary

NM_006180

Melanoma

NP_006171

1
G261R
Ig-likeC2-
0.0500
0.9000
1.0000
0.9836
0.9976
0.0395
Lung Adenocarcinoma

NM_006180
type1

NP_006171

1
I264M
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9976
0.0402
Head and Neck

NM_006180
type1

Squamous Cell

NP_006171

Carcinoma

2
C266S
Ig-likeC2-
0.1000
0.9000
1.0000
1.0000
0.9976
0.0898
Colon

C266Y
type1

Adenocarcinoma;

NM_006180

Bladder Urothelial

NP_006171

Carcinoma

5
A268V
Ig-likeC2-
0.2500
0.9000
0.0000
1.0000
0.9976
0.0000
Lung Adenocarcinoma;

NM_006180
type1

Gastroesophageal

NP_006171

Junction

Adenocarcinoma;

Rectum

Adenocarcinoma

1
V272E
Ig-likeC2-
0.0500
0.9000
0.0000
1.0000
0.9925
0.0000
Lung Adenocarcinoma

NM_006180
type1

NP_006171

2
V279A
Ig-likeC2-
0.1000
0.9000
0.0000
0.9836
0.9927
0.0000
Lung Non-Small Cell

N280I
type1

Lung Carcinoma;

NM_006180

Lymph Node

NP_006171

Lymphoma Follicular

Lymphoma

3
A286P

0.1500
0.0500
1.0000
1.0000
0.9986
0.0070
Liver Hepatocellular

A286T

Carcinoma;

NM_006180

Unknown Primary

NP_006171

Adenocarcinoma

1
I289V

0.0500
0.0500
1.0000
1.0000
0.9950
0.0000
Stomach

NM_006180

Adenocarcinoma

NP_006171

6
L292I

0.3000
0.0500
1.0000
1.0000
0.9840
0.0133
Unknown Primary

E293D

Squamous Cell

E293K

Carcinoma;

S294F

Unknown Primary

NM_006180

Carcinoma;

NP_006171

Unknown Primary

Malignant Neoplasm

7
E293D

0.3500
0.0500
0.5714
1.0000
0.9861
0.0089
Unknown Primary

E293K

Squamous Cell

S294F

Carcinoma;

P295S

Bone Marrow Multiple

NM_006180

Myeloma;

NP_006171

Skin Melanoma

5
S294F
Ig-likeC2-
0.2500
0.9000
0.4000
1.0000
0.9986
0.0861
Bone Marrow Multiple

P295S
type2

Myeloma;

T296I

Skin Melanoma;

NM_006180

Unknown Primary

NP_006171

Melanoma

1
P304L
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9986
0.0449
Colon Adenocarcinoma

NM_006180
type2

NP_006171

2
N310del
Ig-likeC2-
0.1000
0.9000
1.0000
1.0000
0.9964
0.0802
Lung Adenocarcinoma;

P311H
type2

Head and Neck

NM_006180

Neuroblastoma

NP_006171

5
A314E
Ig-likeC2-
0.2500
0.9000
1.0000
0.9672
0.9984
0.0610
Colon

A314G
type2

Adenocarcinoma;

A314V

Lung Non-Small Cell

L315F

Lung Carcinoma;

NM_006180

Unknown Primary

NP_006171

Undifferentiated

Neuroendocrine

Carcinoma

1
Y319C
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9945
0.0448
Lung Non-Small Cell

NM_006180
type2

Lung Carcinoma

NP_006171

2
G321V
Ig-likeC2-
0.1000
0.9000
1.0000
1.0000
0.9984
0.0899
Unknown Primary

NM_006180
type2

Adenocarcinoma

NP_006171

1
E326D
Ig-likeC2-
0.0500
0.9000
0.0000
1.0000
0.9666
0.0000
Lung Adenocarcinoma

NM_006180
type2

NP_006171

1
K328Q
Ig-likeC2-
0.0500
0.9000
1.0000
0.9672
0.9945
0.0387
Lymph Node

NM_006180
type2

Lymphoma Diffuse

NP_006171

Large B Cell

2
C331F
Ig-likeC2-
0.1000
0.9000
0.0000
1.0000
0.9984
0.0000
Lung Adenocarcinoma;

C331Y
type2

Uterus

NM_006180

Leiomyosarcoma

NP_006171

1
H335L
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9945
0.0400
Lung Adenocarcinoma

NM_006180
type2

NP_006171

2
E341K
Ig-likeC2-
0.1000
0.9000
1.0000
1.0000
0.9964
0.0897
Colon

E341V
type2

Adenocarcinoma;

NM_006180

Gallbladder Glomus

NP_006171

Tumor

1
H343D
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9984
0.0449
Pancreas Carcinoma

NM_006180
type2

NP_006171

3
D349Y
Ig-likeC2-
0.1500
0.9000
1.0000
1.0000
0.4799
0.0648
Lung Adenocarcinoma;

N350I
type2

Unknown Primary

N350K

Adenocarcinoma;

NM_006180

Adrenal Gland Cortical

NP_006171

Carcinoma

1
M354I
Ig-likeC2-
0.0500
0.9000
1.0000
1.0000
0.9984
0.0402
Skin Melanoma

NM_006180
type2

NP_006171

2
G357R
Ig-likeC2-
0.1000
0.9000
1.0000
1.0000
0.9984
0.0851
Stomach

D358Y
type2

Adenocarcinoma;

NM_006180

Unknown Primary

NP_006171

Melanoma

1
D370Y

0.0500
0.0500
1.0000
1.0000
0.9984
0.0025
Lung Adenocarcinoma

NM_006180

NP_006171

1
Q373L

0.0500
0.0500
1.0000
1.0000
0.9945
0.0025
Liver

NM_006180

Cholangiocarcinoma

NP_006171

1
H377Y

0.0500
0.0500
1.0000
1.0000
0.9984
0.0025
Skin Squamous Cell

NM_006180

Carcinoma;

NP_006171

2
M379T

0.1000
0.0500
0.0000
1.0000
0.9945
0.0000
Lung Adenocarcinoma;

M379V

Bladder Urothelial

NM_006180

Carcinoma

NP_006171

7
D385G

0.3500
0.0500
0.1429
0.9836
0.7950
0.0018
Colon

D386N

Adenocarcinoma;

G387C

Lung Adenocarcinoma;

NM_006180

Breast Invasive Ductal

NP_006171

Carcinoma

7
D386N

0.3500
0.0500
0.5714
0.9836
0.7731
0.0069
Lung Adenocarcinoma;

G387C

Colon

A388V

Adenocarcinoma;

NM_006180

Breast Carcinoma

NP_006171

3
G387C

0.1500
0.0500
1.0000
1.0000
0.8177
0.0061
Lung Adenocarcinoma;

A388V

Breast Carcinoma;

N389I

Lung Large Cell

NM_006180

Carcinoma

NP_006171

3
A388V

0.1500
0.0500
1.0000
1.0000
0.5854
0.0044
Breast Carcinoma;

N389I

Unknown Primary

P390R

Squamous Cell

NM_006180

Carcinoma;

NP_006171

Lung Large Cell

Carcinoma

4
D394H

0.2000
0.0500
1.0000
1.0000
0.9535
0.0033
Colon

D394N

Adenocarcinoma;

D394Y

Unknown Primary

V395del

Adenocarcinoma;

NM_006180

Bladder Urothelial

NP_006171

Carcinoma

1
E398K

0.0500
0.0500
1.0000
1.0000
0.9960
0.0025
Unknown Primary

NM_006180

Melanoma

NP_006171

3
G401A

0.1500
0.0500
1.0000
1.0000
0.9815
0.0000
Lung Adenocarcinoma;

G401E

Skin Melanoma;

G401R

Soft Tissue

NM_006180

Liposarcoma

NP_006171

3
G408R

0.1500
0.0500
1.0000
0.9672
0.9985
0.0000
Lung Adenocarcinoma;

NM_006180

Breast Invasive Ductal

NP_006171

Carcinoma

1
T410N

0.0500
0.0500
1.0000
0.9836
0.9989
0.0002
Bone Marrow Lymph

NM_006180

Proliferative Disease

NP_006171

1
S414I

0.0500
0.0500
1.0000
1.0000
0.9740
0.0024
Lung Adenocarcinoma

NM_006180

NP_006171

1
E416G

0.0500
0.0500
1.0000
0.9836
0.7364
0.0000
Thymus Thymoma

NM_006180

Lymphocytic

NP_006171

1
S419F

0.0500
0.0500
1.0000
1.0000
0.9989
0.0012
Breast Carcinoma

NM_006180

NP_006171

2
T423I

0.1000
0.0500
1.0000
1.0000
0.3050
0.0000
Brain Glioblastoma;

T423S

Uterus Endometrial

NM_006180

Adenocarcinoma

NP_006171

Endometrioid

10
T426I

0.5000
0.0500
0.5000
0.8689
0.8171
0.0000
Skin Melanoma;

G427S

Lung Adenocarcinoma;

R428Q

Colon Adenocarcinoma

NM_006180

NP_006171

6
H430Y

0.3000
0.0500
1.0000
0.7869
0.9989
0.0000
Colon

NM_006180

Adenocarcinoma;

NP_006171

Bone Marrow Multiple

Myeloma;

Liver

Cholangiocarcinoma

3
S432L

0.1500
0.0500
1.0000
1.0000
0.9989
0.0000
Lung Adenocarcinoma;

NM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma;

Gallbladder

Adenocarcinoma

1
A435V

0.0500
0.0500
1.0000
1.0000
0.9989
0.0025
Soft Tissue

NM_006180

Paraganglioma

NP_006171

4
A440S

0.2000
0.0500
1.0000
0.9836
0.9989
0.0044
Colon

A440T

Adenocarcinoma;

A440V

Breast Carcinoma;

NM_006180

Breast Ductal

NP_006171

Carcinoma in Situ

2
V442L

0.1000
0.0500
1.0000
0.9344
0.9989
0.0000
Lung Adenocarcinoma

V442M

NM_006180

NP_006171

1
C446Y

0.0500
0.0500
1.0000
1.0000
0.9989
0.0003
Lung Adenocarcinoma

NM_006180

NP_006171

1
V449I

0.0500
0.0500
1.0000
0.9344
0.9736
0.0000
Pancreas Ductal

NM_006180

Adenocarcinoma

NP_006171

1
F452L

0.0500
0.0500
1.0000
1.0000
0.9247
0.0021
Stomach

NM_006180

Adenocarcinoma

NP_006171

2
L454I

0.1000
0.0500
1.0000
1.0000
0.9191
0.0000
Bladder Urothelial

K455N

Carcinoma;

NM_006180

Stomach

NP_006171

Adenocarcinoma

2
R458G

0.1000
0.0500
1.0000
1.0000
0.9946
0.0000
Liver

NM_006180

Cholangiocarcinoma;

NP_006171

Uterus Endometrial

Adenocarcinoma

Endometrioid

3
S460F

0.1500
0.0500
1.0000
1.0000
0.9737
0.0073
Lung Adenocarcinoma;

S460T

Liver

S460Y

Cholangiocarcinoma;

NM_006180

Soft Tissue Synovial

NP_006171

Sarcoma

1
M464V

0.0500
0.0500
1.0000
1.0000
0.9953
0.0000
Soft Tissue Sarcoma

NM_006180

NP_006171

3
V475A

0.1500
0.0500
0.0000
1.0000
0.9916
0.0000
Lung Adenocarcinoma;

K476E

Skin Squamous Cell

K476I

Carcinoma;

NM_006180

Lung Adenosquamous

NP_006171

Carcinoma

7
G480D

0.3500
0.0500
1.0000
0.9344
0.9733
0.0000
Lung Adenocarcinoma;

V481I

Colon

G482R

Adenocarcinoma;

G482VNM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma

7
V481I

0.3500
0.0500
0.7143
0.9344
0.9734
0.0035
Lung Non-Small Cell

G482R

Lung Carcinoma;

G482V

Lung Adenocarcinoma;

P483T

Colon Adenocarcinoma

NM_006180

NP_006171

4
G482R

0.2000
0.0500
0.5000
0.9836
0.9982
0.0043
Colon

G482V

Adenocarcinoma;

P483T

Kidney Renal Cell

A484T

Carcinoma;

NM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma

3
V486F

0.1500
0.0500
0.0000
0.9672
0.9984
0.0000
Colon

V486I

Adenocarcinoma;

NM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma;

Bladder Urothelial

Carcinoma

2
P496R

0.1000
0.0500
0.0000
1.0000
0.9984
0.0000
Lung Adenocarcinoma;

P496S

Brain Astrocytoma;

NM_006180

NP_006171

2
H498N

0.1000
0.0500
1.0000
1.0000
0.9984
0.0047
Lung Adenocarcinoma;

H498Y

Skin Melanoma

NM_006180

NP_006171

1
S501C

0.0500
0.0500
1.0000
1.0000
0.9984
0.0025
Gastroesophageal

NM_006180

Junction

NP_006171

Adenocarcinoma

1
G503W

0.0500
0.0500
1.0000
1.0000
0.9982
0.0022
Lung Adenocarcinoma

NM_006180

NP_006171

3
P514L

0.1500
0.0500
1.0000
1.0000
0.9984
0.0024
Unknown Primary

P514S

Adenocarcinoma;

D515N

Stomach

NM_006180

Adenocarcinoma;

NP_006171

Unknown Primary

Urothelial Carcinoma

1
V517I

0.0500
0.0500
1.0000
1.0000
0.9984
0.0000
Gastroesophageal

NM_006180

Junction

NP_006171

Adenocarcinoma

1
I519del

0.0500
0.0500
0.0000
1.0000
0.9944
0.0000
Breast Carcinoma

NM_006180

NP_006171

1
M521L

0.0500
0.0500
1.0000
1.0000
0.9944
0.0012
Gastroesophageal

NM_006180

Junction

NP_006171

Adenocarcinoma

1
I524F

0.0500
0.0500
1.0000
1.0000
0.9944
0.0025
Unknown Primary

NM_006180

Carcinoma

NP_006171

1
E528K

0.0500
0.0500
0.0000
1.0000
0.9984
0.0000
Skin Melanoma

NM_006180

NP_006171

1
P530L

0.0500
0.0500
1.0000
1.0000
0.9984
0.0012
Colon Adenocarcinoma

NM_006180

NP_006171

2
Q539H

0.1000
0.0500
1.0000
1.0000
0.5850
0.0029
Liver

NM_006180

Cholangiocarcinoma;

NP_006171

Lung Small Cell

Undifferentiated

Carcinoma

1
F545V

0.0500
0.0500
1.0000
1.0000
0.9939
0.0000
Lung Adenocarcinoma

NM_006180

NP_006171

1
Q547R

0.0500
0.0500
1.0000
1.0000
0.9957
0.0000
Lung Adenocarcinoma

NM_006180

NP_006171

1
I549M

0.0500
0.0500
1.0000
1.0000
0.9989
0.0022
Breast Ductal

NM_006180

Carcinoma in Situ

NP_006171

2
H552Q

0.1000
0.0500
0.0000
1.0000
0.6398
0.0000
Lung Adenocarcinoma;

N553S

Soft Tissue

NM_006180

Leiomyosarcoma

NP_006171

4
R558K
Protein
0.2000
1.0000
0.2500
1.0000
0.9810
0.0400
Lung Adenocarcinoma;

E559D
kinase

Brain Glioblastoma;

E559K

Unknown Primary

NM_006180

Melanoma

NP_006171

5
G561S
Protein
0.2500
1.0000
0.4000
1.0000
0.9989
0.0925
Skin Melanoma;

E562K
kinase

Lung Adenocarcinoma;

G563R

Bladder Urothelial

G563V

Carcinoma

NM_006180

NP_006171

5
E562K
Protein
0.2500
1.0000
0.4000
1.0000
0.9989
0.0696
Skin Melanoma;

G563R
kinase

Breast Invasive Ductal

G563V

Carcinoma;

A564T

Bladder Urothelial

NM_006180

Carcinoma

NP_006171

1
G566E
Protein
0.0500
1.0000
1.0000
1.0000
0.9989
0.0499
Unknown Primary

NM_006180
kinase

Melanoma

NP_006171

1
F569L
Protein
0.0500
1.0000
1.0000
1.0000
0.9987
0.0250
Gastroesophageal

NM_006180
kinase

Junction

NP_006171

Adenocarcinoma

1
Y574H
Protein
0.0500
1.0000
1.0000
1.0000
0.9954
0.0000
Bone Sarcoma

NM_006180
kinase

NP_006171

6
C577S
Protein
0.3000
1.0000
0.5000
1.0000
0.9653
0.0905
Ovary Epithelial

P578H
kinase

Carcinoma;

P578L

Lung Adenocarcinoma;

P578S

Bladder Urothelial

P578T

Carcinoma

E579D

NM_006180

NP_006171

6
P578H
Protein
0.3000
1.0000
0.5000
1.0000
0.9647
0.0181
Lung Adenocarcinoma;

P578L
kinase

Bladder Urothelial

P578S

Carcinoma;

P578T

Ovary Epithelial

E579D

Carcinoma

Q580P

NM_006180

NP_006171

3
E579D
Protein
0.1500
1.0000
1.0000
1.0000
0.9469
0.0187
Colon

Q580P
kinase

Adenocarcinoma;

D581N

Peritoneum Serous

NM_006180

Carcinoma;

NP_006171

Stomach

Leiomyosarcoma

3
Q580P
Protein
0.1500
1.0000
1.0000
1.0000
0.9965
0.0629
Colon

D581N
kinase

Adenocarcinoma;

K582T

Stomach

NM_006180

Adenocarcinoma

NP_006171

Intestinal Type;

Peritoneum Serous

Carcinoma

1
L584F
Protein
0.0500
1.0000
1.0000
0.9836
0.9987
0.0000
Breast Carcinoma

NM_006180
kinase

NP_006171

1
T589S
Protein
0.0500
1.0000
1.0000
1.0000
0.9969
0.0000
Rectum

NM_006180
kinase

Adenocarcinoma

NP_006171

1
D592A
Protein
0.0500
1.0000
1.0000
1.0000
0.9906
0.0495
Unknown Primary

NM_006180
kinase

Melanoma

NP_006171

1
D595E
Protein
0.0500
1.0000
0.0000
1.0000
0.9456
0.0000
Lung Small Cell

NM_006180
kinase

Undifferentiated

NP_006171

Carcinoma

4
R598C
Protein
0.2000
1.0000
1.0000
1.0000
0.9953
0.1991
Lung Adenocarcinoma;

R598S
kinase

Breast Carcinoma;

K599M

Soft Tissue Sarcoma

D600H

NM_006180

NP_006171

3
H602N
Protein
0.1500
1.0000
1.0000
1.0000
0.9964
0.1495
Lung Adenocarcinoma;

R603S
kinase

Lung Squamous Cell

NM_006180

Carcinoma;

NP_006171

Unknown Primary

Sarcomatoid

Carcinoma

1
L608M
Protein
0.0500
1.0000
1.0000
1.0000
0.9344
0.0047
Breast Invasive Ductal

NM_006180
kinase

Carcinoma

NP_006171

3
H615L
Protein
0.1500
1.0000
0.0000
1.0000
0.9912
0.0000
Lung Non-Small Cell

H615Y
kinase

Lung Carcinoma;

I616T

Liver Hepatocellular

NM_006180

Carcinoma;

NP_006171

Kidney Sarcomatoid

Carcinoma

1
K618R
Protein
0.0500
1.0000
1.0000
0.9836
0.9887
0.0049
Colon Adenocarcinoma

NM_006180
kinase

NP_006171

1
V622I
Protein
0.0500
1.0000
1.0000
0.9508
0.9961
0.0000
Unknown Primary

NM_006180
kinase

Carcinoma

NP_006171

3
V624L
Protein
0.1500
1.0000
0.0000
1.0000
0.9961
0.0000
Breast Carcinoma;

V624M
kinase

Skin Melanoma;

E625K

Unknown Primary

NM_006180

Carcinoma

NP_006171

1
D627N
Protein
0.0500
1.0000
1.0000
0.9836
0.9961
0.0000
Stomach

NM_006180
kinase

Adenocarcinoma

NP_006171

2
L629I
Protein
0.1000
1.0000
0.0000
1.0000
0.9924
0.0000
Lung Non-Small Cell

I630V
kinase

Lung Carcinoma;

NM_006180

Lung Squamous Cell

NP_006171

Carcinoma

1
V632I
Protein
0.0500
1.0000
1.0000
1.0000
0.9961
0.0498
Skin Melanoma

NM_006180
kinase

NP_006171

1
E634Q
Protein
0.0500
1.0000
1.0000
1.0000
0.9961
0.0498
Gastroesophageal

NM_006180
kinase

Junction

NP_006171

Adenocarcinoma

3
H638L
Protein
0.1500
1.0000
0.0000
1.0000
0.9950
0.0000
Lung Adenocarcinoma;

G639R
kinase

Colon

G639V

Adenocarcinoma;

NM_006180

Uterus Endometrial

NP_006171

Adenocarcinoma

1
R646M
Protein
0.0500
1.0000
1.0000
1.0000
0.9961
0.0249
Soft Tissue

NM_006180
kinase

Perivascular Epithelioid

NP_006171

Cell Tumor

2
H648Q
Protein
0.1000
1.0000
1.0000
1.0000
0.0229
0.0017
Breast Carcinoma;

G649S
kinase

Unknown Primary

NM_006180

Melanoma

NP_006171

5
A652V
Protein
0.2500
1.0000
1.0000
0.9508
0.9963
0.0947
Lung Adenocarcinoma;

V653M
kinase

Breast Invasive Ductal

L654V

Carcinoma;

NM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma

5
A656D
Protein
0.2500
1.0000
0.0000
1.0000
0.9952
0.0000
Lung Adenocarcinoma;

E657K
kinase

Breast Carcinoma;

E657Q

Lung Non-Small Cell

G658D

Lung Carcinoma

NM_006180

NP_006171

2
P660L
Protein
0.1000
1.0000
1.0000
0.0000
0.9952
0.0000
Lung Adenocarcinoma;

P660T
kinase

Head and Neck

NM_006180

Adenoid Cystic

NP_006171

Carcinoma

2
T662M
Protein
0.1000
1.0000
1.0000
1.0000
0.9952
0.0995
Liver

NM_006180
kinase

Cholangiocarcinoma;

NP_006171

Lymph Node

Lymphoma Mediastinal

B-Cell(Pmbcl)

5
L664M
Protein
0.2500
1.0000
1.0000
0.9508
0.9902
0.1997
Lung Adenocarcinoma;

T665M
kinase

Colon

T665S

Adenocarcinoma;

Q666L

Head and Neck

Q666R

Squamous Cell

NM_006180

Carcinoma

NP_006171

1
Q668L
Protein
0.0500
1.0000
1.0000
1.0000
0.9869
0.0000
Colon Adenocarcinoma

NM_006180
kinase

NP_006171

3
L670M
Protein
0.1500
1.0000
1.0000
1.0000
0.9646
0.0381
Lung Adenocarcinoma;

H671R
kinase

Lung Squamous Cell

NM_006180

Carcinoma;

NP_006171

Bone Marrow

Leukemia Non-

Lymphocytic Acute

Myelocytic

2
A673G
Protein
0.1000
1.0000
1.0000
1.0000
0.9580
0.0000
Colon

Q674H
kinase

Adenocarcinoma;

NM_006180

Lung Non-Small Cell

NP_006171

Lung Carcinoma

6
A677T
Protein
0.3000
1.0000
0.6667
1.0000
0.9952
0.1765
Colon

A678T
kinase

Adenocarcinoma;

A678V

Gastroesophageal

G679D

Junction

NM_006180

Adenocarcinoma;

NP_006171

Bladder Urothelial

Carcinoma

6
A678T
Protein
0.3000
1.0000
0.6667
0.9836
0.9952
0.1636
Gastroesophageal

A678V
kinase

Junction

G679D

Adenocarcinoma;

M680I

Colon

NM_006180

Adenocarcinoma;

NP_006171

Bladder Urothelial

Carcinoma

1
Y682C
Protein
0.0500
1.0000
1.0000
1.0000
0.9869
0.0493
Adrenal Gland Cortical

NM_006180
kinase

Carcinoma

NP_006171

7
A684E
Protein
0.3500
1.0000
1.0000
1.0000
0.9952
0.0697
Lung Adenocarcinoma;

A684T
kinase

Head and Neck

A684V

Squamous Cell

S685Y

Carcinoma;

NM_006180

Pancreas Ductal

NP_006171

Adenocarcinoma

2
V689M
Protein
0.1000
1.0000
1.0000
1.0000
0.9952
0.0890
Uterus Endometrial

NM_006180
kinase

Adenocarcinoma

NP_006171

Endometrioid;

Breast Lobular

Carcinoma in Situ

3
R691C
Protein
0.1500
1.0000
1.0000
1.0000
0.9952
0.1335
Other;

D692N
kinase

Ovary Serous

NM_006180

Carcinoma;

NP_006171

Unknown Primary

Adenocarcinoma

5
C698R
Protein
0.2500
1.0000
0.0000
1.0000
0.7190
0.0000
Lung Adenocarcinoma;

C698W
kinase

Breast Carcinoma;

L699P

Breast Invasive Ductal

V700F

Carcinoma

NM_006180

NP_006171

1
E702D
Protein
0.0500
1.0000
1.0000
1.0000
0.9952
0.0498
Lung Non-Small Cell

NM_006180
kinase

Lung Carcinoma

NP_006171

1
V706M
Protein
0.0500
1.0000
1.0000
1.0000
0.9952
0.0050
Skin Melanoma

NM_006180
kinase

NP_006171

3
G709R
Protein
0.1500
1.0000
1.0000
1.0000
0.9952
0.0149
Lung Non-Small Cell

D710Y
kinase

Lung Carcinoma;

NM_006180

Uterus Endometrial

NP_006171

Adenocarcinoma

Papillary Serous;

Leukemia Lymphocytic

4
S714A
Protein
0.2000
1.0000
0.2500
1.0000
0.9931
0.0421
Skin Melanoma;

R715Q
kinase

Lung Non-Small Cell

R715W

Lung Carcinoma;

D716N

Prostate Acinar

NM_006180

Adenocarcinoma

NP_006171

4
V725G
Protein
0.2000
1.0000
0.5000
1.0000
0.9979
0.0862
Lung Adenocarcinoma;

G726C
kinase

Lung Non-Small Cell

G727D

Lung Carcinoma;

NM_006180

Liver Hepatocellular

NP_006171

Carcinoma

1
T729S
Protein
0.0500
1.0000
1.0000
1.0000
0.9954
0.0498
Lung Squamous Cell

NM_006180
kinase

Carcinoma

NP_006171

2
M736I
Protein
0.1000
1.0000
0.0000
1.0000
0.9987
0.0000
Lung Adenocarcinoma;

P737T
kinase

Unknown Primary

NM_006180

Sarcomatoid

NP_006171

Carcinoma

3
I741N
Protein
0.1500
1.0000
1.0000
0.9836
0.9957
0.0788
Lung Adenocarcinoma;

I741V
kinase

Breast Invasive Ductal

M742L

Carcinoma;

NM_006180

Lung Sarcoma

NP_006171

1
R744K
Protein
0.0500
1.0000
1.0000
1.0000
0.9988
0.0050
Skin Basal Cell

NM_006180
kinase

Carcinoma

NP_006171

10
F746I
Protein
0.5000
1.0000
0.7000
0.9836
0.9985
0.2458
Colon

T747M
kinase

Adenocarcinoma;

T748M^1,2,3

Liver Hepatocellular

NM_006180

Carcinoma^1,2,3;

NP_006171

Bladder Urothelial

Carcinoma; Large

Intestine/Colon

Carcinoma²; Lymphoid

Neoplasm³

10
T747M
Protein
0.5000
1.0000
0.4000
0.9836
0.9988
0.1424
Colon

T748M
kinase

Adenocarcinoma;

E749K

Bladder Urothelial

NM_006180

Carcinoma;

NP_006171

Lung Adenocarcinoma

6
T748M
Protein
0.3000
1.0000
0.0000
0.9836
0.9988
0.0000
Lung Adenocarcinoma;

E749K
kinase

Colon

S750N

Adenocarcinoma;

NM_006180

Liver Hepatocellular

NP_006171

Carcinoma

1
V752I
Protein
0.0500
1.0000
0.0000
1.0000
0.9989
0.0000
Colon Adenocarcinoma

NM_006180
kinase

NP_006171

4
S754T
Protein
0.2000
1.0000
0.5000
1.0000
0.9989
0.0946
Lung Adenocarcinoma;

L755M
kinase

Lung Non-Small Cell

G756W

Lung Carcinoma;

NM_006180

Unknown Primary

NP_006171

Adenocarcinoma

4
V758E
Protein
0.2000
1.0000
0.0000
1.0000
0.9981
0.0000
Lung Adenocarcinoma;

V758L
kinase

Ovary Serous

V758M

Carcinoma;

NM_006180

Unknown Primary

NP_006171

Carcinoma

5
W760R
Protein
0.2500
1.0000
0.0000
1.0000
0.9894
0.0000
Lung Adenocarcinoma;

E761D
kinase

Colon

E761Q

Adenocarcinoma;

I762M

Unknown Primary

NM_006180

Melanoma

NP_006171

2
G766D
Protein
0.1000
1.0000
0.0000
1.0000
0.9989
0.0000
Brain Glioblastoma;

G766S
kinase

Lung Small Cell

NM_006180

Undifferentiated

NP_006171

Carcinoma

1
P769T
Protein
0.0500
1.0000
0.0000
1.0000
0.9989
0.0000
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

2
L773M
Protein
0.1000
1.0000
0.0000
1.0000
0.9989
0.0000
Colon Adenocarcinoma

NM_006180
kinase

NP_006171

1
E777Q
Protein
0.0500
1.0000
1.0000
1.0000
0.9989
0.0050
Lymph Node

NM_006180
kinase

Lymphoma Diffuse

NP_006171

Large B Cell

1
I779M
Protein
0.0500
1.0000
1.0000
1.0000
0.1928
0.0000
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

3
I782M
Protein
0.1500
1.0000
1.0000
1.0000
0.8857
0.0000
Lung Adenocarcinoma;

T783I
kinase

Unknown Primary

Q784H

Carcinoma;

NM_006180

Brain Meningioma

NP_006171

3
T783I
Protein
0.1500
1.0000
1.0000
1.0000
0.9455
0.0473
Unknown Primary

Q784H
kinase

Carcinoma;

G785V

Uterus Endometrial

NM_006180

Adenocarcinoma;

NP_006171

Brain Meningioma

4
Q784H
Protein
0.2000
1.0000
1.0000
0.9672
0.9587
0.1757
Colon

G785V
kinase

Adenocarcinoma;

R786Q

Unknown Primary

NM_006180

Carcinoma;

NP_006171

Uterus Endometrial

Adenocarcinoma

4
G785V
Protein
0.2000
1.0000
1.0000
0.9672
0.9981
0.1795
Colon

R786Q
kinase

Adenocarcinoma;

V787F

Uterus Endometrial

NM_006180

Adenocarcinoma;

NP_006171

Bile Duct

Adenocarcinoma

4
R786Q
Protein
0.2000
1.0000
1.0000
0.9672
0.8640
0.1539
Colon

V787F
kinase

Adenocarcinoma;

L788M

Stomach

NM_006180

Adenocarcinoma;

NP_006171

Bile Duct

Adenocarcinoma

3
V787F
Protein
0.1500
1.0000
1.0000
1.0000
0.8193
0.1229
Colon

L788M
kinase

Adenocarcinoma;

Q789E

Stomach

NM_006180

Adenocarcinoma;

NP_006171

Bile Duct

Adenocarcinoma

4
R792C
Protein
0.2000
1.0000
0.2500
0.9344
0.9780
0.0026
Lung Adenocarcinoma;

T793A
kinase

Brain

T793M

Medulloblastoma;

NM_006180

Breast Neuroendocrine

NP_006171

Carcinoma

1
P795T
Protein
0.0500
1.0000
1.0000
1.0000
0.9981
0.0050
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

1
E797K
Protein
0.0500
1.0000
1.0000
1.0000
0.9986
0.0050
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

1
Y799N
Protein
0.0500
1.0000
0.0000
1.0000
0.9949
0.0000
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

1
M802L
Protein
0.0500
1.0000
1.0000
1.0000
0.9949
0.0445
Esophagus

NM_006180
kinase

Adenocarcinoma

NP_006171

3
G804E
Protein
0.1500
1.0000
1.0000
1.0000
0.9973
0.1247
Colon

C805R
kinase

Adenocarcinoma;

C805Y

Lung Non-Small Cell

NM_006180

Lung Carcinoma;

NP_006171

Unknown Primary

Adenocarcinoma

1
P810T
Protein
0.0500
1.0000
1.0000
1.0000
0.9986
0.0250
Lung Adenocarcinoma

NM_006180
kinase

NP_006171

1
M812I
Protein
0.0500
1.0000
0.0000
0.9836
0.8600
0.0000
Skin Melanoma

NM_006180
kinase

NP_006171

1
G818D
Protein
0.0500
1.0000
1.0000
1.0000
0.8511
0.0426
Appendix

NM_006180
kinase

Adenocarcinoma

NP_006171

3
T821N
Protein
0.1500
1.0000
1.0000
1.0000
0.9986
0.0867
Liver Hepatocellular

T821S
kinase

Carcinoma;

L822F

Gastroesophageal

NM_006180

Junction

NP_006171

Adenocarcinoma;

Uterus Endometrial

Adenocarcinoma

Papillary Serous

1
N825D

0.0500
0.0500
1.0000
0.9508
0.9949
0.0021
Bone Marrow Multiple

NM_006180

Myeloma

NP_006171

2
A829S

0.1000
0.0500
1.0000
1.0000
0.9986
0.0045
Lung Adenocarcinoma;

NM_006180

Unknown Primary

NP_006171

Adenocarcinoma

2
P831L

0.1000
0.0500
1.0000
0.9672
0.9986
0.0000
Lung Non-Small Cell

NM_006180

Lung Carcinoma;

NP_006171

Pancreas Ductal

Adenocarcinoma

¹Pediatric Cancer Gene Database, pedican.bioinfo-minzhao.org/gene_mutation.cgi?gene=4915, downloaded on May 31, 2016.

²Endometrial Cancer Gene Database, ecgene.bioinfo-minzhao.org/gene_mutation.cgi?gene=4915, downloaded on May 31, 2016.

³Catalog of Somatic Mutations in Cancer (COSMIC) database, cancer.sanger.ac.uk/cosmic/mutation/overview?id=1636266, downloaded on May 31, 2016.

TABLE 3

Detected TrkB Protein Mutations Resulting from NTRK2 Point Mutations

Detected in Cancer Biopsy Samples (Confirmed Expression)

Mutated
Mutations

Hotspot
Domain
co-Alteration
Exac
Conservation
Total

Disease
Samples
Domain
Score
Score
Score
Score
Score
Score

5
A314E
Ig-like C2-type 2
0.25
0.90
1.00
0.97
1.00
0.22

A314G

A314V

L315F

2
V689M
Protein kinase
0.10
1.00
1.00
1.00
1.00
0.10

5
M240I
Ig-like C2-type 1
0.25
0.90
0.40
1.00
1.00
0.09

N241D

E242K

1
I264M
Ig-like C2-type 1
0.05
0.90
1.00
1.00
1.00
0.04

4
A440S

0.20
0.05
1.00
0.98
1.00
0.01

A440T

A440V

10
T426I, G427S, R428Q

0.50
0.05
0.50
0.87
0.82
0.01

3
G401A, G401E, G401R

0.15
0.05
1.00
1.00
0.98
0.01

TABLE 4

Detected TrkC Protein Mutations Resulting from NTRK3 Point Mutations Detected in Cancer Biopsy Samples

Mutated
Mutations

Hotspot
Domain
co-Alteration
Exac
Conservation
Total

Samples
Ref. Transcript/Protein
Domain
Score
Score
Score
Score
Score
Score
Disease

3
S4C

0.1500
0.0500
1.0000
1.0000
0.9813
0.0069
Lung Adenocarcinoma;

S4F

Lung Squamous Cell

L5I

Carcinoma

NM_001012338

NP_001012338

5
P7L

0.2500
0.0500
0.4000
1.0000
0.9773
0.0033
Lung Adenocarcinoma;

P7R

Colon

A8D

Adenocarcinoma;

K9E

Unknown Primary

K9N

Adenocarcinoma

NM_001012338

NP_001012338

1
R14P

0.0500
0.0500
1.0000
1.0000
0.9813
0.0025
Breast Carcinoma

NM_001012338

NP_001012338

1
G19E

0.0500
0.0500
0.0000
1.0000
0.7246
0.0000
Colon Adenocarcinoma

NM_001012338

NP_001012338

4
V21F

0.2000
0.0500
1.0000
0.0000
0.7777
0.0000
Colon

V21I

Adenocarcinoma;

NM_001012338

Breast Invasive Ductal

NP_001012338

Carcinoma;

Head and Neck

Squamous Cell

Carcinoma

1
Y25C

0.0500
0.0500
1.0000
1.0000
0.9688
0.0000
Lymphoma Follicular

NM_001012338

Lymphoma

NP_001012338

1
G27A

0.0500
0.0500
1.0000
1.0000
0.9858
0.0025
Breast Carcinoma

NM_001012338

NP_001012338

4
N35S

0.2000
0.0500
0.2500
1.0000
0.7479
0.0017
Skin Melanoma;

C36W

Liver Hepatocellular

V37A

Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma

1
S39R

0.0500
0.0500
1.0000
1.0000
0.9691
0.0022
Lung Adenocarcinoma

NM_001012338

NP_001012338

7
C45W

0.3500
0.0500
1.0000
0.9508
0.9581
0.0000
Lung Adenocarcinoma;

R46P

Breast Carcinoma;

R46W

Breast Invasive Ductal

NM_001012338

Carcinoma

NP_001012338

2
P48L

0.1000
0.0500
0.0000
1.0000
0.9775
0.0000
Lung Adenocarcinoma;

D49G

Bladder Urothelial

NM_001012338

Carcinoma

NP_001012338

1
P55S

0.0500
0.0500
1.0000
1.0000
0.9860
0.0022
Uterus Endometrial

NM_001012338

Adenocarcinoma

NP_001012338

Endometrioid

2
G63W

0.1000
0.0500
1.0000
1.0000
0.8998
0.0045
Unknown Primary

N64K

Carcinoma

NM_001012338

NP_001012338

2
G67E

0.1000
0.0500
1.0000
0.9672
0.9885
0.0000
Colon

NM_001012338

Adenocarcinoma;

NP_001012338

Breast Carcinoma

1
A69T

0.0500
0.0500
1.0000
1.0000
0.0000
0.0000
Colon Adenocarcinoma

NM_001012338

NP_001012338

2
I71V

0.1000
0.0500
1.0000
0.6885
0.0000
0.0000
Breast Carcinoma;

NM_001012338

Liver

NP_001012338

Cholangiocarcinoma

3
D75G

0.1500
0.0500
0.0000
1.0000
0.9835
0.0000
Colon

D75N

Adenocarcinoma;

I76T

Thyroid Papillary

NM_001012338

Carcinoma

NP_001012338

3
R78K

0.1500
0.0500
1.0000
0.9672
0.9545
0.0012
Lung Squamous Cell

R78S

Carcinoma;

NM_001012338

Bladder Urothelial

NP_001012338

Carcinoma;

Skin Basal Cell

Carcinoma

2
S82F

0.1000
0.0500
0.0000
1.0000
0.9859
0.0000
Skin Melanoma

I83V

NM_001012338

NP_001012338

2
I85M

0.1000
0.0500
0.0000
1.0000
0.4043
0.0000
Lung Adenocarcinoma;

NM_001012338

Colon Adenocarcinoma

NP_001012338

9
R89C

0.4500
0.0500
0.0000
0.9344
0.9578
0.0000
Colon

R89H

Adenocarcinoma;

R89S

Lung Adenocarcinoma;

S90N

Breast Carcinoma

NM_001012338

NP_001012338

4
N95S

0.2000
0.0500
1.0000
0.9836
0.8553
0.0024
Colon

A96S

Adenocarcinoma;

A96T

Uterus Endometrial

NM_001012338

Adenocarcinoma;

NP_001012338

Bladder Carcinoma

4
D98G

0.2000
0.0500
0.5000
0.9836
0.9928
0.0016
Lung Adenocarcinoma;

D98N

Breast Carcinoma;

M99I

Skin Melanoma

NM_001012338

NP_001012338

1
L101I

0.0500
0.0500
1.0000
1.0000
0.9950
0.0022
Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

1
K111N
LRR 1
0.0500
0.3000
1.0000
1.0000
0.9968
0.0015
Breast Carcinoma

NM_001012338

NP_001012338

5
S113T
LRR 1
0.2500
0.3000
1.0000
1.0000
0.9930
0.0577
Lung Adenocarcinoma;

G114E

Colon

L115F

Adenocarcinoma;

L115P

Head and Neck

L115R

Squamous Cell

NM_001012338

Carcinoma

NP_001012338

9
G114E
LRR 1
0.4500
0.3000
0.6667
0.9508
0.9057
0.0597
Colon

L115F

Adenocarcinoma;

L115P

Unknown Primary

L115R

Melanoma;

R116Q

Lung Adenocarcinoma

R116W

NM_001012338

NP_001012338

9
L115F
LRR 1
0.4500
0.3000
0.6667
0.9344
0.8790
0.0627
Colon

L115P

Adenocarcinoma;

L115R

Unknown Primary

R116Q

Melanoma;

R116W

Lung Adenocarcinoma

S117N

NM_001012338

NP_001012338

5
Q119H
LRR 1
0.2500
0.3000
1.0000
1.0000
0.9500
0.0629
Lung Adenocarcinoma;

Q119K

Lung Squamous Cell

P120H

Carcinoma;

R121G

Liver Hepatocellular

R121K

Carcinoma

NM_001012338

NP_001012338

4
F123L
LRR 1
0.2000
0.3000
0.0000
1.0000
0.9799
0.0000
Lung Adenocarcinoma;

A124V

Colon

K125E

Adenocarcinoma;

K125N

Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

4
A124V
LRR 1
0.2000
0.3000
0.0000
1.0000
0.7283
0.0000
Lung Adenocarcinoma;

K125E

Colon

K125N

Adenocarcinoma;

N126K

Pancreas Ductal

NM_001012338

Adenocarcinoma

NP_001012338

4
K125E

0.2000
0.0500
0.0000
1.0000
0.7283
0.0000
Lung Adenocarcinoma;

K125N

Colon

N126K

Adenocarcinoma;

P127H

Pancreas Ductal

NM_001012338

Adenocarcinoma

NP_001012338

6
R130C
LRR 2
0.3000
0.3000
1.0000
0.9344
0.9523
0.0464
Lung Adenocarcinoma;

R130H

Breast Carcinoma;

NM_001012338

Breast Invasive Ductal

NP_001012338

Carcinoma

2
N133H
LRR 2
0.1000
0.3000
1.0000
1.0000
0.9920
0.0149
Lung Adenocarcinoma;

L134Q

Unknown Primary

NM_001012338

Adenocarcinoma

NP_001012338

7
R138Q
LRR 2
0.3500
0.3000
1.0000
0.8197
0.9974
0.0000
Lung Adenocarcinoma;

R138W

Colon

NM_001012338

Adenocarcinoma;

NP_001012338

Lung Non-Small Cell

Lung Carcinoma

1
T140N
LRR 2
0.0500
0.3000
0.0000
1.0000
0.9974
0.0000
Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

5
F147L
LRR 2
0.2500
0.3000
1.0000
0.8033
0.9974
0.0000
Lung Adenocarcinoma;

Q148H

Breast Invasive Ductal

T149M

Carcinoma;

T149R

Stomach

NM_001012338

Adenocarcinoma

NP_001012338

6
L152I

0.3000
0.0500
1.0000
0.9508
0.9974
0.0129
Lung Adenocarcinoma;

R153Q

Colon

E154K

Adenocarcinoma;

NM_001012338

Breast Carcinoma

NP_001012338

4
Q156H

0.2000
0.0500
1.0000
1.0000
0.1641
0.0006
Lung Adenocarcinoma;

Q156R

Skin Melanoma;

L157M

Bile Duct

E158K

Adenocarcinoma

NM_001012338

NP_001012338

4
L157M

0.2000
0.0500
0.5000
1.0000
0.6264
0.0026
Lung Adenocarcinoma;

E158K

Skin Melanoma;

Q159H

Lung Non-Small Cell

Q159K

Lung Carcinoma

NM_001012338

NP_001012338

1
F161I
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9933
0.0149
Breast Ductal

NM_001012338

Carcinoma in Situ

NP_001012338

6
N163T
LRRCT
0.3000
0.3000
0.5000
0.9836
0.9948
0.0000
Lung Adenocarcinoma;

C164G

Unknown Primary

C164S

Adenocarcinoma;

S165N

Colon Adenocarcinoma

NM_001012338

NP_001012338

1
R169S
LRRCT
0.0500
0.3000
0.0000
1.0000
0.9979
0.0000
Lung Adenocarcinoma

NM_001012338

NP_001012338

2
M171L
LRRCT
0.1000
0.3000
1.0000
0.9508
0.9956
0.0000
Lung Adenocarcinoma

Q172H

NM_001012338

NP_001012338

1
W174L
LRRCT
0.0500
0.3000
0.0000
1.0000
0.9979
0.0000
Lung Adenocarcinoma

NM_001012338

NP_001012338

1
E176K
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9979
0.0150
Skin Melanoma

NM_001012338

NP_001012338

4
G178E
LRRCT
0.2000
0.3000
1.0000
1.0000
0.9979
0.0599
Unknown Primary

G178V

Melanoma;

E179K

Lung Small Cell

NM_001012338

Undifferentiated

NP_001012338

Carcinoma;

Unknown Primary

Malignant Neoplasm

3
S184C
LRRCT
0.1500
0.3000
1.0000
0.9836
0.4394
0.0179
Lung Adenocarcinoma;

S184N

Bone Marrow Multiple

S184R

Myeloma;

NM_001012338

Skin Melanoma

NP_001012338

5
Y188C
LRRCT
0.2500
0.3000
0.0000
1.0000
0.9951
0.0000
Lung Adenocarcinoma;

Y188F

Lung Squamous Cell

Y188H

Carcinoma

C189F

NM_001012338

NP_001012338

1
A192T
LRRCT
0.0500
0.3000
1.0000
1.0000
0.5408
0.0041
Gastroesophageal

NM_001012338

Junction

NP_001012338

Adenocarcinoma

5
G194D
LRRCT
0.2500
0.3000
1.0000
1.0000
0.9748
0.0658
Brain Glioblastoma;

S195C

Lung Non-Small Cell

S195F

Lung Carcinoma;

Q196K

Bladder Urothelial

NM_001012338

Carcinoma

NP_001012338

6
L199H
LRRCT
0.3000
0.3000
0.0000
0.9180
0.9301
0.0000
Colon

L199P

Adenocarcinoma;

L199V

Breast Invasive Ductal

F200V

Carcinoma;

R201C

Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

4
F200V
LRRCT
0.2000
0.3000
0.2500
0.9180
0.8985
0.0077
Colon

R201C

Adenocarcinoma;

M202I

Brain Glioblastoma;

NM_001012338

Lung Non-Small Cell

NP_001012338

Lung Carcinoma

1
S205G
LRRCT
0.0500
0.3000
1.0000
1.0000
0.9933
0.0133
Esophagus

NM_001012338

Adenocarcinoma

NP_001012338

10
D208E
LRRCT
0.5000
0.3000
0.4000
0.3279
0.9648
0.0148
Soft Tissue Sarcoma;

D208N

Breast Invasive Ductal

L209I

Carcinoma;

L209P

Lung Non-Small Cell

L209R

Lung Carcinoma

L209V

P210S

NM_001012338

NP_001012338

1
I212M
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9978
0.0449
Lung Non-Small Cell

NM_001012338
type 1

Lung Carcinoma

NP_001012338

1
S215T
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9978
0.0000
Lung Adenocarcinoma

NM_001012338
type 1

NP_001012338

5
V217A
Ig-like C2-
0.2500
0.9000
1.0000
0.9672
0.9145
0.0000
Lung Non-Small Cell

V217I
type 1

Lung Carcinoma;

N218S

Colon

NM_001012338

Adenocarcinoma;

NP_001012338

Pancreas Carcinoma

7
V221I
Ig-like C2-
0.3500
0.9000
1.0000
0.9180
0.8870
0.1832
Unknown Primary

R222Q
type 1

Melanoma;

E223D

Skin Melanoma;

NM_001012338

Uterus Endometrial

NP_001012338

Adenocarcinoma

Endometrioid

1
A227T
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9587
0.0043
Skin Basal Cell

NM_001012338
type 1

Carcinoma

NP_001012338

1
T230S
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9929
0.0400
Lung Squamous Cell

NM_001012338
type 1

Carcinoma

NP_001012338

2
N232S
Ig-like C2-
0.1000
0.9000
0.0000
0.9836
0.9953
0.0000
Brain Glioblastoma;

G233F
type 1

Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

2
G235E
Ig-like C2-
0.1000
0.9000
0.0000
1.0000
0.9745
0.0000
Skin Melanoma;

G235R
type 1

Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

5
P239H
Ig-like C2-
0.2500
0.9000
0.2000
1.0000
0.9968
0.0381
Lung Adenocarcinoma;

P239S
type 1

Bladder Urothelial

P239T

Carcinoma;

D240G

Unknown Primary

D240H

Melanoma

NM_001012338

NP_001012338

6
D242N
Ig-like C2-
0.3000
0.9000
0.5000
1.0000
0.9584
0.1120
Lung Small Cell

W243C
type 1

Carcinoma;

I244T

Lung Adenocarcinoma;

NM_001012338

Colon Adenocarcinoma

NP_001012338

3
L248M
Ig-like C2-
0.1500
0.9000
0.0000
1.0000
0.9724
0.0000
Lung Adenocarcinoma;

Q249H
type 1

Colon

NM_001012338

Adenocarcinoma;

NP_001012338

Gastroesophageal

Junction

Adenocarcinoma

5
N252S
Ig-like C2-
0.2500
0.9000
0.6000
0.9836
0.9789
0.0808
Head and Neck

N252T
type 1

Squamous Cell

T253N

Carcinoma;

H254Q

Lung Non-Small Cell

NM_001012338

Lung Carcinoma;

NP_001012338

Unknown Primary

Carcinoma

4
T253N
Ig-like C2-
0.2000
0.9000
0.0000
1.0000
0.9767
0.0000
Lung Non-Small Cell

H254Q
type 1

Lung Carcinoma;

Q255H

Head and Neck

NM_001012338

Squamous Cell

NP_001012338

Carcinoma;

Lung Sarcoma

4
H254Q
Ig-like C2-
0.2000
0.9000
0.0000
1.0000
0.9766
0.0000
Lung Non-Small Cell

Q255H
type 1

Lung Carcinoma;

T256N

Unknown Primary

NM_001012338

Adenocarcinoma;

NP_001012338

Lung Sarcoma

1
W260R
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9919
0.0045
Lung Adenocarcinoma

NM_001012338
type 1

NP_001012338

1
N262S
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9919
0.0399
Ovary Carcinoma

NM_001012338
type 1

NP_001012338

1
I266V
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9919
0.0399
Kidney Renal Cell

NM_001012338
type 1

Carcinoma

NP_001012338

8
T269A
Ig-like C2-
0.4000
0.9000
0.6250
0.9672
0.9701
0.1004
Lung Adenocarcinoma;

T269M
type 1

Head and Neck

L270M

Squamous Cell

L270Q

Carcinoma;

L270V

Skin Melanoma

V271L

V271M

NM_001012338

NP_001012338

2
V273M
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9727
0.0438
Lung Adenocarcinoma;

V273del
type 1

Rectum Squamous

NM_001012338

Cell Carcinoma

NP_001012338

5
E276D
Ig-like C2-
0.2500
0.9000
1.0000
0.9836
0.9454
0.1586
Breast Invasive Ductal

D277E
type 1

Carcinoma;

D277G

Unknown Primary

D277N

Adenocarcinoma;

NM_001012338

Stomach

NP_001012338

Adenocarcinoma

1
G279D
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9534
0.0429
Head and Neck

NM_001012338
type 1

Squamous Cell

NP_001012338

Carcinoma

12
T281I
Ig-like C2-
0.6000
0.9000
1.0000
0.9508
0.9594
0.2223
Lung

T281P
type 1

Adenocarcinoma^2,3,4,12;

L282M^2,3

Unknown Primary

T283A

Carcinoma;

T283K^2,4,12

Breast Invasive Ductal

T283M

Carcinoma

NM_001012338

NP_001012338

2
E287D
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9751
0.0816
Uterus Endometrial

E287Q
type 1

Adenocarcinoma

NM_001012338

Papillary Serous;

NP_001012338

Eye Intraocular

Melanoma

2
V289A
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9919
0.0670
Ovary Serous

V290A
type 1

Carcinoma;

NM_001012338

Uterus Endometrial

NP_001012338

Adenocarcinoma

Endometrioid

5
M292I
Ig-like C2-
0.2500
0.9000
0.4000
1.0000
0.9714
0.0261
Breast Invasive Ductal

M292V
type 1

Carcinoma;

S293R

Unknown Primary

N294T

Adenocarcinoma;

NM_001012338

Thyroid Papillary

NP_001012338

Carcinoma

3
S296I
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.9809
0.1208
Head and Neck

S296R
type 1

Squamous Cell

V297I

Carcinoma;

NM_001012338

Lung Squamous Cell

NP_001012338

Carcinoma;

Bone Marrow

Leukemia Non-

Lymphocytic Acute

Myelocytic

1
L299del
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9967
0.0401
Colon Adenocarcinoma

NM_001012338
type 1

NP_001012338

1
V301F

0.0500
0.0500
1.0000
1.0000
0.9967
0.0025
Lung Adenocarcinoma

NM_001012338

NP_001012338

18
P304L

0.9000
0.0500
0.6667
0.7213
0.9965
0.0000
Unknown Primary

P304S

Melanoma;

P304T

Colon

P305Q

Adenocarcinoma;

P305R

Breast Invasive Ductal

P305S

Carcinoma

P305T

R306C

R306H

R306P

NM_001012338

NP_001012338

6
V308L

0.3000
0.0500
0.0000
0.9672
0.9677
0.0000
Lung Adenocarcinoma;

S309I

Breast Invasive Ductal

NM_001012338

Carcinoma;

NP_001012338

Lung Non-Small Cell

Lung Carcinoma

6
E312K
Ig-like C2-
0.3000
0.9000
0.0000
1.0000
0.9858
0.0000
Lung Adenocarcinoma;

E312Q
type 2

Colon

P313T

Adenocarcinoma;

E314A

Skin Melanoma

E314D

E314Q

NM_001012338

NP_001012338

4
R316C
Ig-like C2-
0.2000
0.9000
0.0000
0.9016
0.9965
0.0000
Colon

R316H
type 2

Adenocarcinoma;

NM_001012338

Breast Invasive Ductal

NP_001012338

Carcinoma;

Skin Melanoma

1
C320F
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9965
0.0401
Lung Non-Small Cell

NM_001012338
type 2

Lung Carcinoma

NP_001012338

6
E322A
Ig-like C2-
0.3000
0.9000
0.1667
1.0000
0.9942
0.0388
Lung Adenocarcinoma;

E322K
type 2

Unknown Primary

E322Q

Melanoma;

F323L

Unknown Primary

NM_001012338

Carcinoma

NP_001012338

8
V325M
Ig-like C2-
0.4000
0.9000
0.5000
0.8689
0.9965
0.1185
Lung Adenocarcinoma;

R326C
type 2

Colon

R326G

Adenocarcinoma;

R326H

Breast Carcinoma

R326L

R326P

NM_001012338

NP_001012338

5
N328S
Ig-like C2-
0.2500
0.9000
1.0000
0.9836
0.9951
0.1101
Lung Adenocarcinoma;

P329N
type 2

Colon

P329S

Adenocarcinoma;

P330Q

Skin Melanoma

NM_001012338

NP_001012338

2
T332M
Ig-like C2-
0.1000
0.9000
1.0000
0.7377
0.9965
0.0592
Colon

NM_001012338
type 2

Adenocarcinoma;

NP_001012338

Esophagus

Adenocarcinoma

1
H334Q
Ig-like C2-
0.0500
0.9000
0.0000
0.9836
0.7412
0.0000
Lung Adenocarcinoma

NM_001012338
type 2

NP_001012338

2
L336R
Ig-like C2-
0.1000
0.9000
1.0000
1.0000
0.9897
0.0000
Ovary Serous

H337R
type 2

Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma

3
G339K
Ig-like C2-
0.1500
0.9000
0.0000
1.0000
0.9170
0.0000
Lung Adenocarcinoma;

Q340H Q340K
type 2

Rectum

NM_001012338

Adenocarcinoma;

NP_001012338

Skin Squamous Cell

Carcinoma

5
R343L
Ig-like C2-
0.2500
0.9000
1.0000
1.0000
0.9924
0.0837
Lung Adenocarcinoma;

E344G
type 2

Colon

E344V

Adenocarcinoma;

S345F

Bladder Urothelial

NM_001012338

Carcinoma

NP_001012338

5
E344G
Ig-like C2-
0.2500
0.9000
1.0000
1.0000
0.9924
0.1954
Colon

E344V
type 2

Adenocarcinoma;

S345F

Bladder Urothelial

K346N

Carcinoma;

NM_001012338

Gastroesophageal

NP_001012338

Junction

Adenocarcinoma

6
H349Y
Ig-like C2-
0.3000
0.9000
1.0000
1.0000
0.6005
0.1564
Lung Adenocarcinoma;

V350E
type 2

Bone Marrow Multiple

E351D

Myeloma;

NM_001012338

Lung Squamous Cell

NP_001012338

Carcinoma

3
Y353F
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.9920
0.1269
Lung Adenocarcinoma;

Q354K
type 2

Lung Small Cell

NM_001012338

Undifferentiated

NP_001012338

Carcinoma

7
G356E
Ig-like C2-
0.3500
0.9000
0.0000
1.0000
0.9168
0.0000
Skin Melanoma;

G356R
type 2

Lung Adenocarcinoma;

G356Y

Unknown Primary

E357D

Melanoma

NM_001012338

NP_001012338

2
S359F
Ig-like C2-
0.1000
0.9000
0.0000
1.0000
0.9960
0.0000
Skin Melanoma;

NM_001012338
type 2

Eye Intraocular

NP_001012338

Squamous Cell

Carcinoma

3
G361N
Ig-like C2-
0.1500
0.9000
0.0000
1.0000
0.9960
0.0000
Lung Non-Small Cell

G361S
type 2

Lung Carcinoma;

C362F

Unknown Primary

NM_001012338

Squamous Cell

NP_001012338

Carcinoma;

Skin Adnexal

Carcinoma

1
L364F
Ig-like C2-
0.0500
0.9000
1.0000
0.9836
0.9960
0.0441
Colon Adenocarcinoma

NM_001012338
type 2

NP_001012338

2
H370N
Ig-like C2-
0.1000
0.9000
0.0000
1.0000
0.9953
0.0000
Lung Adenocarcinoma;

NM_001012338
type 2

Skin Melanoma

NP_001012338

1
N372K
Ig-like C2-
0.0500
0.9000
0.0000
1.0000
0.9204
0.0000
Colon Adenocarcinoma

NM_001012338
type 2

NP_001012338

1
Y376N
Ig-like C2-
0.0500
0.9000
1.0000
1.0000
0.9869
0.0444
Lung Adenocarcinoma

NM_001012338
type 2

NP_001012338

6
L378V
Ig-like C2-
0.3000
0.9000
1.0000
0.9836
0.9551
0.0884
Breast Invasive Ductal

I379V
type 2

Carcinoma;

A380P

Head and Neck

A380V

Squamous Cell

NM_001012338

Carcinoma;

NP_001012338

Skin Melanoma

3
N382H
Ig-like C2-
0.1500
0.9000
1.0000
1.0000
0.9880
0.0930
Rectum

N382I
type 2

Adenocarcinoma;

N382T

Esophagus

NM_001012338

Adenocarcinoma;

NP_001012338

Soft Tissue Synovial

Sarcoma

1
L384M

0.0500
0.0500
1.0000
1.0000
0.9319
0.0021
Lung Adenocarcinoma

NM_001012338

NP_001012338

5
N388K

0.2500
0.0500
1.0000
0.8361
0.9829
0.0000
Colon

Q389E

Adenocarcinoma;

Q389H

Brain Glioblastoma;

NM_001012338

Unknown Primary

NP_001012338

Adenocarcinoma

9
N392S

0.4500
0.0500
1.0000
0.7213
0.3707
0.0000
Lung Adenocarcinoma;

G393D

Skin Melanoma;

G393S

Soft Tissue Sarcoma

H394Q

NM_001012338

NP_001012338

5
L396I

0.2500
0.0500
1.0000
0.9836
0.9498
0.0106
Lung Non-Small Cell

K397N

Lung Carcinoma;

E398D

Lung Adenocarcinoma;

E398K

Bladder Urothelial

NM_001012338

Carcinoma

NP_001012338

5
K397N

0.2500
0.0500
0.4000
0.9836
0.9498
0.0042
Lung Non-Small Cell

E398D

Lung Carcinoma;

E398K

Lung Adenocarcinoma;

P399L

Skin Melanoma

NM_001012338

NP_001012338

5
P401Q

0.2500
0.0500
1.0000
1.0000
0.9966
0.0119
Skin Melanoma;

P401S

Unknown Primary

NM_001012338

Melanoma;

NP_001012338

Unknown Primary

Malignant Neoplasm

4
T404M

0.2000
0.0500
0.2500
0.8689
0.9940
0.0020
Lung Adenocarcinoma;

T404S

Brain Glioblastoma;

D405N

Lung Small Cell

D405V

Undifferentiated

NM_001012338

Carcinoma

NP_001012338

1
I408M

0.0500
0.0500
1.0000
1.0000
0.0000
0.0000
Head and Neck

NM_001012338

Squamous Cell

NP_001012338

Carcinoma

5
D411E

0.2500
0.0500
1.0000
0.9344
0.4354
0.0048
Breast Carcinoma;

D411N

Lung Adenocarcinoma;

E412K

Skin Melanoma

NM_001012338

NP_001012338

4
P415H

0.2000
0.0500
1.0000
1.0000
0.9974
0.0093
Lung Non-Small Cell

P415S

Lung Carcinoma;

T416I

Unknown Primary

P417L

Melanoma;

NM_001012338

Head and Neck

NP_001012338

Neuroblastoma

3
T416I

0.1500
0.0500
1.0000
1.0000
0.9959
0.0075
Stomach

P417L

Adenocarcinoma;

P418H

Unknown Primary

NM_001012338

Melanoma;

NP_001012338

Ovary Carcinosarcoma

2
V421L

0.1000
0.0500
1.0000
1.0000
0.9974
0.0050
Lung Adenocarcinoma;

NM_001012338

Ovary Serous

NP_001012338

Carcinoma

1
H423Q

0.0500
0.0500
1.0000
1.0000
0.7735
0.0002
Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

2
P425S

0.1000
0.0500
1.0000
0.9836
0.9733
0.0048
Skin Melanoma;

E426K

Unknown Primary

NM_001012338

Melanoma

NP_001012338

4
T429I

0.2000
0.0500
0.5000
1.0000
0.9960
0.0037
Lung Adenocarcinoma;

F430V

Lung Small Cell

G431V

Undifferentiated

G431W

Carcinoma;

NM_001012338

Brain

NP_001012338

Oligodendroglioma

1
S433F

0.0500
0.0500
1.0000
1.0000
0.9978
0.0025
Skin Melanoma

NM_001012338

NP_001012338

4
A435E

0.2000
0.0500
1.0000
1.0000
0.9965
0.0093
Lung Adenocarcinoma;

V436A

Breast Invasive Ductal

V436F

Carcinoma;

G437E

Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

1
A439P

0.0500
0.0500
1.0000
1.0000
0.9978
0.0025
Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

4
V448A

0.2000
0.0500
0.2500
1.0000
0.9685
0.0021
Lung Adenocarcinoma;

L449P

Stomach

F450L

Adenocarcinoma;

NM_001012338

Lung Large Cell

NP_001012338

Neuroendocrine

Carcinoma

8
L449P

0.4000
0.0500
0.3750
0.9672
0.7053
0.0013
Lung Adenocarcinoma;

F450L

Colon

V451I

Adenocarcinoma;

NM_001012338

Kidney Renal Cell

NP_001012338

Carcinoma

13
F450L

0.6500
0.0500
0.6154
0.9672
0.8075
0.0043
Lung Adenocarcinoma;

V451I

Colon

M452I

Adenocarcinoma;

M452K

Kidney Renal Cell

M452L

Carcinoma

M452V

NM_001012338

NP_001012338

2
K455N

0.1000
0.0500
1.0000
1.0000
0.9693
0.0036
Head and Neck

K455R

Squamous Cell

NM_001012338

Carcinoma;

NP_001012338

Soft Tissue

Angiosarcoma

9
G457C

0.4500
0.0500
0.0000
0.9672
0.9645
0.0000
Lung Adenocarcinoma;

G457V

Colon

R458P

Adenocarcinoma;

R459G

Skin Melanoma

R459W

NM_001012338

NP_001012338

7
R458P

0.3500
0.0500
0.0000
0.9672
0.9546
0.0000
Lung Adenocarcinoma;

R459G

Colon

R459W

Adenocarcinoma;

S460T

Skin Melanoma

NM_001012338

NP_001012338

8
R459G

0.4000
0.0500
0.0000
0.9672
0.9584
0.0000
Lung Adenocarcinoma;

R459W

Colon

S460T

Adenocarcinoma;

K461R

Skin Melanoma

NM_001012338

NP_001012338

5
G463R

0.2500
0.0500
1.0000
0.9836
0.9865
0.0109
Head and Neck

G463V

Squamous Cell

M464I

Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma;

Uterus Endometrial

Adenocarcinoma

Endometrioid

8
G466C

0.4000
0.0500
1.0000
0.9672
0.9903
0.0027
Breast Invasive Ductal

P467H

Carcinoma;

P467S

Ovary Serous

V468L

Carcinoma;

V468M

Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

8
P467H

0.4000
0.0500
1.0000
0.9672
0.9964
0.0028
Lung Non-Small Cell

P467S

Lung Carcinoma;

V468L

Breast Invasive Ductal

V468M

Carcinoma;

A469D

Ovary Serous

NM_001012338

Carcinoma

NP_001012338

2
G473C

0.1000
0.0500
1.0000
1.0000
0.9912
0.0050
Lung Adenocarcinoma

E474G

NM_001012338

NP_001012338

3
S477L

0.1500
0.0500
0.0000
1.0000
0.9953
0.0000
Lung Adenocarcinoma;

A478G

Anus Squamous Cell

NM_001012338

Carcinoma

NP_001012338

3
G487C

0.1500
0.0500
0.0000
0.9672
0.9557
0.0000
Colon

G487S

Adenocarcinoma;

I488T

Brain Glioblastoma;

NM_001012338

Uterus Endometrial

NP_001012338

Adenocarcinoma

Endometrioid

7
T490K

0.3500
0.0500
0.0000
0.8361
0.9635
0.0000
Colon

T490M

Adenocarcinoma;

P491H

Lung Adenocarcinoma;

S492L

Breast Invasive Ductal

NM_001012338

Carcinoma

NP_001012338

1
L494M

0.0500
0.0500
0.0000
1.0000
0.3947
0.0000
Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

13
A496E

0.6500
0.0500
0.6154
0.7869
0.9890
0.0008
Lung Adenocarcinoma;

A496V

Skin Squamous Cell

G497R

Carcinoma;

G497V

Breast Invasive Ductal

G497W

Carcinoma

NM_001012338

NP_001012338

5
D499N

0.2500
0.0500
1.0000
0.8525
0.9972
0.0000
Lung Adenocarcinoma;

NM_001012338

Stomach

NP_001012338

Adenocarcinoma;

Unknown Primary

Melanoma

1
V501L

0.0500
0.0500
0.0000
1.0000
0.9972
0.0000
Lung Adenocarcinoma

NM_001012338

NP_001012338

11
T506A

0.5500
0.0500
0.7273
0.8852
0.9634
0.0094
Lung Adenocarcinoma;

T506S

Colon

R507C

Adenocarcinoma;

R507H

Kidney Renal Cell

R507P

Carcinoma

I508T

NM_001012338

NP_001012338

11
R507C

0.5500
0.0500
0.7273
0.9016
0.9484
0.0086
Colon

R507H

Adenocarcinoma;

R507P

Lung Adenocarcinoma;

I508T

Brain Glioblastoma

P509L

P509S

NM_001012338

NP_001012338

4
I511T

0.2000
0.0500
1.0000
1.0000
0.8334
0.0077
Lung Adenocarcinoma;

E512K

Gastroesophageal

N513I

Junction

N513K

Adenocarcinoma;

NM_001012338

Uterus Endometrial

NP_001012338

Adenocarcinoma

Endometrioid

5
E512K

0.2500
0.0500
1.0000
1.0000
0.8571
0.0036
Lung Adenocarcinoma;

N513I

Breast Invasive Ductal

N513K

Carcinoma;

P514H

Gastroesophageal

P514S

Junction

NM_001012338

Adenocarcinoma

NP_001012338

1
Y516F

0.0500
0.0500
1.0000
1.0000
0.8632
0.0022
Unknown Primary

NM_001012338

Carcinoma

NP_001012338

8
R518C

0.4000
0.0500
0.2500
0.9016
0.9563
0.0011
Colon

R518H

Adenocarcinoma;

Q519E

Brain Glioblastoma;

Q519L

Lung Adenocarcinoma

G520E

NM_001012338

NP_001012338

4
Q519E

0.2000
0.0500
0.2500
1.0000
0.9834
0.0020
Lung Adenocarcinoma;

Q519L

Colon

G520E

Adenocarcinoma;

H521N

Breast Invasive Ductal

NM_001012338

Carcinoma

NP_001012338

3
G520E

0.1500
0.0500
1.0000
1.0000
0.9799
0.0056
Colon

H521N

Adenocarcinoma;

N522K

Unknown Primary

NM_001012338

Adenocarcinoma;

NP_001012338

Stomach

Adenocarcinoma

Diffuse Type

4
P526A

0.2000
0.0500
0.0000
0.9836
0.9853
0.0000
Lung Adenocarcinoma;

P526Q

Unknown Primary

D527E

Adenocarcinoma

NM_001012338

NP_001012338

1
Y529N

0.0500
0.0500
1.0000
1.0000
0.9913
0.0012
Ovary Epithelial

NM_001012338

Carcinoma

NP_001012338

1
Q531R

0.0500
0.0500
1.0000
0.9836
0.8616
0.0019
Head and Neck

NM_001012338

Squamous Cell

NP_001012338

Carcinoma

6
I533F

0.3000
0.0500
1.0000
1.0000
0.9912
0.0000
Lung Adenocarcinoma;

I533L

Breast Invasive Ductal

K534E

Carcinoma;

K534R

Head and Neck

R535M

Squamous Cell

NM_001012338

Carcinoma

NP_001012338

5
K534E

0.2500
0.0500
0.4000
1.0000
0.9940
0.0044
Lung Adenocarcinoma;

K534R

Unknown Primary

R535M

Melanoma

R536I

R536T

NM_001012338

NP_001012338

5
R535M

0.2500
0.0500
0.4000
1.0000
0.9967
0.0044
Lung Adenocarcinoma;

R536I

Lung Squamous Cell

R536T

Carcinoma;

D537E

Unknown Primary

D537Y

Melanoma

NM_001012338

NP_001012338

5
R536I

0.2500
0.0500
0.4000
1.0000
0.9954
0.0044
Lung Adenocarcinoma;

R536T

Lung Squamous Cell

D537E

Carcinoma;

D537Y

Unknown Primary

I538N

Melanoma

NM_001012338

NP_001012338

6
D537E
Protein
0.3000
1.0000
1.0000
0.9672
0.9956
0.2375
Skin Melanoma^2,6;

D537Y^2,5
kinase

Lung Squamous Cell

I538N

Carcinoma;

V539M^2,6

Uterus Endometrial

NM_001012338

Adenocarcinoma

NP_001012338

Endometrioid^2,5; Liver

Carcinoma⁸

5
I538N
Protein
0.2500
1.0000
1.0000
0.9672
0.5976
0.1128
Skin Melanoma;

V539M
kinase

Stomach

L540M

Adenocarcinoma;

NM_001012338

Gallbladder

NP_001012338

Adenocarcinoma

3
R542L
Protein
0.1500
1.0000
1.0000
1.0000
0.4907
0.0678
Kidney Renal Cell

R542del
kinase

Carcinoma;

E543D

Stomach

NM_001012338

Adenocarcinoma;

NP_001012338

Esophagus

Adenocarcinoma

3
G545C
Protein
0.1500
1.0000
1.0000
1.0000
0.9967
0.1229
Lung Adenocarcinoma;

G545D
kinase

Soft Tissue

NM_001012338

Inflammatory

NP_001012338

Myofibroblastic Tumor

3
G547E
Protein
0.1500
1.0000
0.0000
1.0000
0.9967
0.0000
Lung Adenocarcinoma;

G547V
kinase

Breast Carcinoma;

A548_P562del¹

Gastroesophageal

NM_001012338

Junction

NP_001012338

Adenocarcinoma

3
A548_P562del¹
Protein
0.1500
1.0000
1.0000
1.0000
0.9945
0.1243
Breast Carcinoma;

G550R
kinase

Gastroesophageal

K551E

Junction

NM_001012338

Adenocarcinoma;

NP_001012338

Skin Squamous Cell

Carcinoma

11
A548_P562del¹
Protein
0.5500
1.0000
0.8182
0.8852
0.9967
0.1184
Breast Carcinoma;

L560V
kinase

Lung Adenocarcinoma;

P562L

Colon Adenocarcinoma

P562Q

P562R

P562T

NM_001012338

NP_001012338

3
D565H
Protein
0.1500
1.0000
0.0000
1.0000
0.9945
0.0000
Lung Non-Small Cell

K566N
kinase

Lung Carcinoma;

M567T

Lung Squamous Cell

NM_001012338

Carcinoma;

NP_001012338

Pancreas Ductal

Adenocarcinoma

3
K566N
Protein
0.1500
1.0000
0.0000
1.0000
0.9945
0.0000
Lung Non-Small Cell

M567T
kinase

Lung Carcinoma;

L568F

Pancreas Ductal

NM_001012338

Adenocarcinoma;

NP_001012338

Cervix Squamous Cell

Carcinoma

3
M567T
Protein
0.1500
1.0000
0.0000
1.0000
0.9945
0.0000
Lung Non-Small Cell

L568F
kinase

Lung Carcinoma;

V569L

Pancreas Ductal

NM_001012338

Adenocarcinoma;

NP_001012338

Cervix Squamous Cell

Carcinoma

1
K572N
Protein
0.0500
1.0000
0.0000
1.0000
0.9967
0.0000
Lung Adenocarcinoma

NM_001012338
kinase

NP_001012338

7
K575E
Protein
0.3500
1.0000
0.5714
1.0000
0.9493
0.1743
Skin Melanoma;

D576N
kinase

Unknown Primary

P577S

Malignant Neoplasm;

NM_001012338

Unknown Primary

NP_001012338

Undifferentiated

Neuroendocrine

Carcinoma

1
L579M
Protein
0.0500
1.0000
1.0000
1.0000
0.4716
0.0236
Lung Squamous Cell

NM_001012338
kinase

Carcinoma

NP_001012338

9
A581D
Protein
0.4500
1.0000
0.6667
0.9344
0.5079
0.0300
Breast Ductal

R582Q
kinase

Carcinoma in Situ;

R582W

Head and Neck

K583T

Squamous Cell

NM_001012338

Carcinoma;

NP_001012338

Skin Melanoma

14
R582Q
Protein
0.7000
1.0000
0.7857
0.9344
0.5448
0.1703
Skin Melanoma;

R582W
kinase

Unknown Primary

K583T

Melanoma;

D584E

Breast Ductal

D584N

Carcinoma in Situ

NM_001012338

NP_001012338

3
Q586K
Protein
0.1500
1.0000
0.0000
1.0000
0.9955
0.0000
Lung Adenocarcinoma;

Q586L
kinase

Unknown Primary

NM_001012338

Carcinoma

NP_001012338

1
E588Q
Protein
0.0500
1.0000
0.0000
1.0000
0.9973
0.0000
Colon Adenocarcinoma

NM_001012338
kinase

NP_001012338

2
E590D
Protein
0.1000
1.0000
0.0000
0.9672
0.7326
0.0000
Lung Adenocarcinoma;

E590K
kinase

Skin Melanoma

NM_001012338

NP_001012338

1
L592I
Protein
0.0500
1.0000
0.0000
1.0000
0.9973
0.0000
Lung Adenocarcinoma

NM_001012338
kinase

NP_001012338

4
L595P
Protein
0.2000
1.0000
0.0000
1.0000
0.5097
0.0000
Lung Adenocarcinoma;

Q596K
kinase

Unknown Primary

H597N

Adenocarcinoma

H597Q

NM_001012338

NP_001012338

4
Q596K
Protein
0.2000
1.0000
0.0000
1.0000
0.5097
0.0000
Lung Adenocarcinoma

H597N
kinase

H597Q

E598G

NM_001012338

NP_001012338

5
H597N
Protein
0.2500
1.0000
0.0000
1.0000
0.6061
0.0000
Lung Adenocarcinoma;

H597Q
kinase

Uterus Endometrial

E598G

Adenocarcinoma

H599L

Endometrioid

H599Y

NM_001012338

NP_001012338

4
E598G
Protein
0.2000
1.0000
0.0000
1.0000
0.9931
0.0000
Lung Adenocarcinoma;

H599L
kinase

Prostate Acinar

H599Y

Adenocarcinoma;

I600V

Uterus Endometrial

NM_001012338

Adenocarcinoma

NP_001012338

Endometrioid

5
H599L
Protein
0.2500
1.0000
0.4000
1.0000
0.9940
0.0445
Lung Adenocarcinoma;

H599Y
kinase

Prostate Acinar

I600V

Adenocarcinoma;

V601A

Uterus Endometrial

V601I

Adenocarcinoma

NM_001012338

Endometrioid

NP_001012338

4
I600V
Protein
0.2000
1.0000
1.0000
1.0000
0.9931
0.0000
Lung Adenocarcinoma;

V601A
kinase

Colon

V601I

Adenocarcinoma;

K602R

Prostate Acinar

NM_001012338

Adenocarcinoma

NP_001012338

5
V601A
Protein
0.2500
1.0000
1.0000
1.0000
0.9951
0.1113
Lung Adenocarcinoma;

V601I
kinase

Colon

K602R

Adenocarcinoma;

F603L

Lung Non-Small Cell

NM_001012338

Lung Carcinoma

NP_001012338

6
K602R
Protein
0.3000
1.0000
0.5000
1.0000
0.9936
0.1365
Lung Adenocarcinoma;

F603L
kinase

Colon

Y604F

Adenocarcinoma;

Y604H

Lung Non-Small Cell

Y604N

Lung Carcinoma

NM_001012338

NP_001012338

6
F603L
Protein
0.3000
1.0000
0.0000
1.0000
0.9868
0.0000
Lung Adenocarcinoma;

Y604F
kinase

Lung Non-Small Cell

Y604H

Lung Carcinoma;

Y604N

Lung Squamous Cell

G605V

Carcinoma

NM_001012338

NP_001012338

19
C607F
Protein
0.9500
1.0000
0.8421
0.9180
0.9966
0.6144
Lung Adenocarcinoma^{2 (G608C),7};

G608C^2,7
kinase

Head and Neck

G608E

Squamous Cell

G608S^2,8,11,12

Carcinoma;

D609G

Skin Melanoma; Large

D609H

Intestine

D609N^2,9

Adenocarcinoma^{2,12 (G608S),8};

D609V^2,10,12

Pancreas

NM_001012338

Carcinoma^8,12; Urinary

NP_001012338

Tract Carcinoma^{2 (D609N),9};

Kidney Carcinoma⁹;

Upper Aerodigestive

Tract Squamous Cell

Carcinoma^{2 (D609V),10,12};

Colorectal Cancer¹¹

20
G608C^2,7
Protein
1.0000
1.0000
1.0000
0.9180
0.9966
0.7348
Head and Neck

G608E
kinase

Squamous Cell

G608S^2,8,11,12

Carcinoma;

D609G

Skin Melanoma;

D609H

Lung Adenocarcinoma^{2 (G608C),7};

D609N^2,9

Large Intestine

D609V^2,10,12

Adenocarcinoma^{2 (G608S),8,12};

G610R

Pancreas

NM_001012338

Carcinoma^8,12; Urinary

NP_001012338

Tract Carcinoma^{2 (D609N),9};

Kidney Carcinoma⁹;

Upper Aerodigestive

Tract Squamous Cell

Carcinoma^{2 (D609V),10,12};

Colorectal Cancer¹¹

5
P612A
Protein
0.2500
1.0000
1.0000
0.9672
0.9973
0.1531
Bone Marrow Multiple

P612L
kinase

Myeloma;

P612S

Lung Non-Small Cell

P612T

Lung Carcinoma;

NM_001012338

Lung Squamous Cell

NP_001012338

Carcinoma

1
M615I
Protein
0.0500
1.0000
0.0000
1.0000
0.9973
0.0000
Lung Adenocarcinoma

NM_001012338
kinase

NP_001012338

3
K621N
Protein
0.1500
1.0000
0.0000
1.0000
0.9517
0.0000
Lung Adenocarcinoma;

NM_001012338
kinase

Gastroesophageal

NP_001012338

Junction

Adenocarcinoma

3
G623E
Protein
0.1500
1.0000
0.0000
1.0000
0.9973
0.0000
Skin Melanoma;

D624Y
kinase

Lung Non-Small Cell

L625M

Lung Carcinoma;

NM_001012338

Kidney Urothelial

NP_001012338

Carcinoma

3
D624Y
Protein
0.1500
1.0000
1.0000
1.0000
0.9023
0.1015
Lung Non-Small Cell

L625M
kinase

Lung Carcinoma;

N626K

Unknown Primary

NM_001012338

Malignant Neoplasm;

NP_001012338

Kidney Urothelial

Carcinoma

4
L625M
Protein
0.2000
1.0000
1.0000
1.0000
0.9130
0.1217
Ovary Serous

N626K
kinase

Carcinoma;

K627N

Lung Non-Small Cell

K627R

Lung Carcinoma;

NM_001012338

Gastroesophageal

NP_001012338

Junction

Adenocarcinoma

4
N626K
Protein
0.2000
1.0000
1.0000
1.0000
0.9116
0.1367
Ovary Serous

K627N
kinase

Carcinoma;

K627R

Gastroesophageal

F628L

Junction

NM_001012338

Adenocarcinoma;

NP_001012338

Unknown Primary

Melanoma

5
K627N
Protein
0.2500
1.0000
1.0000
1.0000
0.9858
0.1868
Breast Ductal

K627R
kinase

Carcinoma in Situ;

F628L

Ovary Serous

L629F

Carcinoma;

L629I

Gastroesophageal

NM_001012338

Junction

NP_001012338

Adenocarcinoma

4
A631V
Protein
0.2000
1.0000
0.2500
1.0000
0.9961
0.0423
Lung Adenocarcinoma;

H632N
kinase

Head and Neck

H632Y

Squamous Cell

NM_001012338

Carcinoma;

NP_001012338

Skin Melanoma

6
P634L
Protein
0.3000
1.0000
0.6667
1.0000
0.9961
0.1153
Lung Adenocarcinoma;

P634T
kinase

Head and Neck

D635H

Squamous Cell

A636E

Carcinoma;

A636V

Colon Adenocarcinoma

NM_001012338

NP_001012338

7
D635H
Protein
0.3500
1.0000
0.7143
0.9836
0.9940
0.2330
Lung Adenocarcinoma;

A636E
kinase

Head and Neck

A636V

Squamous Cell

M637I

Carcinoma;

M637K

Colon Adenocarcinoma

M637V

NM_001012338

NP_001012338

6
Q643E
Protein
0.3000
1.0000
1.0000
0.0000
0.9858
0.0000
Lung Adenocarcinoma;

Q643H
kinase

Lung Non-Small Cell

P644T

Lung Carcinoma;

R645C

Lymph Node

R645L

Lymphoma Diffuse

R645S

Large B Cell

NM_001012338

NP_001012338

6
A647D
Protein
0.3000
1.0000
0.0000
0.9836
0.9614
0.0000
Lung Adenocarcinoma;

A647I
kinase

Breast Carcinoma;

K648N

Head and Neck

G649S

Squamous Cell

G649V

Carcinoma

NM_001012338

NP_001012338

4
K648N
Protein
0.2000
1.0000
0.0000
1.0000
0.9744
0.0000
Lung Adenocarcinoma;

G649S
kinase

Lung Squamous Cell

G649V

Carcinoma;

E650V

Skin Squamous Cell

NM_001012338

Carcinoma

NP_001012338

4
G649S
Protein
0.2000
1.0000
0.2500
1.0000
0.9925
0.0372
Lung Adenocarcinoma;

G649V
kinase

Skin Squamous Cell

E650V

Carcinoma;

L651P

Nasopharynx and

NM_001012338

Paranasal Sinuses

NP_001012338

Undifferentiated

Carcinoma

5
E650V
Protein
0.2500
1.0000
1.0000
1.0000
0.9932
0.2130
Lung

L651P
kinase

Adenocarcinoma^2,13;

G652R^2,13

Kidney Urothelial

G652V²

Carcinoma;

NM_001012338

Soft Tissue

NP_001012338

Angiosarcoma

6
L651P
Protein
0.3000
1.0000
1.0000
1.0000
0.9937
0.2792
Lung

G652R^2,13
kinase

Adenocarcinoma^2,13;

G652V²

Lung Squamous Cell

L653F

Carcinoma;

L653P

Unknown Primary

NM_001012338

Melanoma

NP_001012338

4
Q655K
Protein
0.2000
1.0000
0.2500
1.0000
0.9943
0.0476
Lung Non-Small Cell

Q655del
kinase

Lung Carcinoma;

M656R

Lung Adenocarcinoma;

NM_001012338

Skin Melanoma

NP_001012338

2
H658N
Protein
0.1000
1.0000
1.0000
1.0000
0.9961
0.0926
Lung Adenocarcinoma;

H658Y
kinase

Unknown Primary

NM_001012338

Melanoma

NP_001012338

2
A660T
Protein
0.1000
1.0000
1.0000
1.0000
0.9925
0.0000
Lung Adenocarcinoma;

S661G
kinase

Colon Adenocarcinoma

NM_001012338

NP_001012338

8
I663V
Protein
0.4000
1.0000
0.2500
1.0000
0.9952
0.0772
Lung Adenocarcinoma;

A664P
kinase

Colon

A664S

Adenocarcinoma;

S665L

Ovary Serous

NM_001012338

Carcinoma

NP_001012338

5
M667I
Protein
0.2500
1.0000
0.0000
1.0000
0.9917
0.0000
Colon

M667L
kinase

Adenocarcinoma;

V668M

Head and Neck

Y669C

Squamous Cell

Y669S

Carcinoma;

NM_001012338

Skin Melanoma

NP_001012338

1
S672Y
Protein
0.0500
1.0000
0.0000
1.0000
0.9961
0.0000
Lung Adenocarcinoma

NM_001012338
kinase

NP_001012338

1
F675S
Protein
0.0500
1.0000
1.0000
1.0000
0.9888
0.0494
Unknown Primary

NM_001012338
kinase

Adenocarcinoma

NP_001012338

7
H677Y
Protein
0.3500
1.0000
0.5714
1.0000
0.9951
0.1792
Pancreas Ductal

R678Q
kinase

Adenocarcinoma;

D679G

Ovary Serous

D679N

Carcinoma;

NM_001012338

Gastroesophageal

NP_001012338

Junction

Adenocarcinoma

1
R683S
Protein
0.0500
1.0000
0.0000
1.0000
0.9961
0.0000
Breast Ductal

NM_001012338
kinase

Carcinoma in Situ

NP_001012338

1
C685F
Protein
0.0500
1.0000
1.0000
1.0000
0.9961
0.0498
Pancreas

NM_001012338
kinase

Neuroendocrine

NP_001012338

Carcinoma

2
V687A
Protein
0.6000
1.0000
0.7500
0.9836
0.9955
0.2385
Unknown Primary

V687I^14,15
kinase

Melanoma;

G688R

Unknown Primary

A689E

Malignant Neoplasm;

A689V

Lung Adenocarcinoma;

NM_001012338

Mouth Carcinoma¹⁴;

NP_001012338

Upper Aerodigestive

Tract Carcinoma¹⁵

6
V693L
Protein
0.3000
1.0000
0.0000
0.9836
0.9925
0.0000
Colon

K694N
kinase

Adenocarcinoma;

I695F

Rectum

I695T

Adenocarcinoma;

NM_001012338

Lung Adenocarcinoma

NP_001012338

7
K694N
Protein
0.3500
1.0000
0.0000
0.9836
0.9930
0.0000
Colon

I695F
kinase

Adenocarcinoma;

I695T

Lung Adenocarcinoma;

G696R

Breast Invasive Ductal

G696W

Carcinoma

NM_001012338

NP_001012338

6
I695F
Protein
0.3000
1.0000
0.0000
0.9836
0.9925
0.0000
Colon

I695T
kinase

Adenocarcinoma;

G696R

Breast Invasive Ductal

G696W

Carcinoma;

D697N

Skin Melanoma

NM_001012338

NP_001012338

5
G699S
Protein
0.2500
1.0000
0.0000
1.0000
0.9946
0.0000
Colon

M700T
kinase

Adenocarcinoma;

S701F

Head and Neck

NM_001012338

Squamous Cell

NP_001012338

Carcinoma;

Skin Melanoma

3
M700T
Protein
0.1500
1.0000
0.0000
1.0000
0.9937
0.0000
Colon

S701F
kinase

Adenocarcinoma;

R702I

Head and Neck

NM_001012338

Squamous Cell

NP_001012338

Carcinoma;

Skin Melanoma

3
V704F
Protein
0.1500
1.0000
0.0000
1.0000
0.9937
0.0000
Head and Neck

Y705N
kinase

Squamous Cell

S706I

Carcinoma;

NM_001012338

Lung Non-Small Cell

NP_001012338

Lung Carcinoma;

Uterus

Leiomyosarcoma

3
Y705N
Protein
0.1500
1.0000
1.0000
0.9344
0.9937
0.1165
Head and Neck

S706I
kinase

Squamous Cell

T707M

Carcinoma;

NM_001012338

Gallbladder

NP_001012338

Adenocarcinoma;

Uterus

Leiomyosarcoma

4
S706I
Protein
0.2000
1.0000
1.0000
0.9344
0.9961
0.1629
Head and Neck

T707M
kinase

Squamous Cell

D708N

Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma;

Gallbladder

Adenocarcinoma

3
Y710C
Protein
0.1500
1.0000
0.0000
1.0000
0.9888
0.0000
Colon

Y710H
kinase

Adenocarcinoma;

NM_001012338

Gastroesophageal

NP_001012338

Junction

Adenocarcinoma;

Pancreas

Neuroendocrine

Carcinoma

2
L712F
Protein
0.1000
1.0000
1.0000
1.0000
0.9797
0.0000
Bladder Urothelial

L712P
kinase

Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma

12
N714S
Protein
0.6000
1.0000
1.0000
0.9508
0.9784
0.0000
Unknown Primary

P715L
kinase

Melanoma;

P715S

Breast Carcinoma;

S716Y

Skin Melanoma

NM_001012338

NP_001012338

6
P715L
Protein
0.3000
1.0000
1.0000
1.0000
0.9875
0.1481
Unknown Primary

P715S
kinase

Melanoma;

S716Y

Breast Invasive Ductal

G717R

Carcinoma;

NM_001012338

Bone Marrow Multiple

NP_001012338

Myeloma

3
D719N
Protein
0.1500
1.0000
1.0000
1.0000
0.9771
0.0000
Skin Melanoma;

F720I
kinase

Unknown Primary

F720L

Adenocarcinoma;

NM_001012338

Lung Small Cell

NP_001012338

Undifferentiated

Carcinoma

2
W723R
Protein
0.1000
1.0000
1.0000
1.0000
0.9797
0.0980
Lung Adenocarcinoma;

C724F
kinase

Skin Squamous Cell

NM_001012338

Carcinoma

NP_001012338

1
V726L
Protein
0.0500
1.0000
0.0000
1.0000
0.9973
0.0000
Skin Melanoma

NM_001012338
kinase

NP_001012338

7
T730N
Protein
0.3500
1.0000
0.7143
1.0000
0.9964
0.2237
Lung Adenocarcinoma;

M731I
kinase

Adrenal Gland Cortical

M731L

Carcinoma;

L732I

Colon Adenocarcinoma

NM_001012338

NP_001012338

11
R735C
Protein
0.5500
1.0000
0.1818
1.0000
0.9973
0.0884
Colon

R735H
kinase

Adenocarcinoma;

R735S

Lung Adenocarcinoma;

W736C

Skin Melanoma

NM_001012338

NP_001012338

3
P738H
Protein
0.1500
1.0000
1.0000
1.0000
0.9817
0.1473
Lung Adenocarcinoma;

P738S
kinase

Ovary Epithelial

NM_001012338

Carcinoma;

NP_001012338

Ovary Clear Cell

Carcinoma

2
S741C
Protein
0.1000
1.0000
1.0000
1.0000
0.9944
0.0099
Skin Melanoma;

S741I
kinase

Lung Squamous Cell

NM_001012338

Carcinoma

NP_001012338

13
Y744F
Protein
0.6500
1.0000
1.0000
0.9672
0.9792
0.5315
Gastroesophageal

R745P
kinase

Junction

R745W

Adenocarcinoma;

K746R

Stomach

K746T

Adenocarcinoma;

NM_001012338

Colon Adenocarcinoma

NP_001012338

1
T749K
Protein
0.0500
1.0000
1.0000
1.0000
0.9967
0.0050
Lung Adenocarcinoma

NM_001012338
kinase

NP_001012338

3
S751N
Protein
0.1500
1.0000
0.0000
1.0000
0.9967
0.0000
Lung Adenocarcinoma;

D752N
kinase

Unknown Primary

V753L

Melanoma

NM_001012338

NP_001012338

4
D752N
Protein
0.2000
1.0000
0.0000
1.0000
0.9967
0.0000
Lung Adenocarcinoma;

V753L
kinase

Lung Squamous Cell

W754C

Carcinoma;

W754L

Unknown Primary

NM_001012338

Melanoma

NP_001012338

5
V753L
Protein
0.2500
1.0000
0.0000
1.0000
0.9967
0.0000
Lung Adenocarcinoma;

W754C
kinase

Breast Carcinoma;

W754L

Lung Squamous Cell

S755R

Carcinoma

NM_001012338

NP_001012338

4
G757E
Protein
0.2000
1.0000
0.2500
1.0000
0.9967
0.0278
Lung Adenocarcinoma;

G757R
kinase

Skin Melanoma;

G757W

Soft Tissue

NM_001012338

Leiomyosarcoma

NP_001012338

2
I759M
Protein
0.1000
1.0000
0.0000
1.0000
0.8619
0.0000
Lung Non-Small Cell

L760F
kinase

Lung Carcinoma;

NM_001012338

Unknown Primary

NP_001012338

Squamous Cell

Carcinoma

4
E762D
Protein
0.2000
1.0000
0.2500
1.0000
0.8792
0.0000
Colon

E762K
kinase

Adenocarcinoma;

NM_001012338

Unknown Primary

NP_001012338

Melanoma;

Lung Small Cell

Undifferentiated

Carcinoma

1
F764I
Protein
0.0500
1.0000
1.0000
1.0000
0.9902
0.0495
Unknown Primary

NM_001012338
kinase

Adenocarcinoma

NP_001012338

1
Y766F
Protein
0.0500
1.0000
1.0000
1.0000
0.9902
0.0443
Lung Small Cell

NM_001012338
kinase

Carcinoma

NP_001012338

7
K768E
Protein
0.3500
1.0000
0.5714
0.8852
0.9902
0.0000
Gastroesophageal

K768R
kinase

Junction

NM_001012338

Adenocarcinoma;

NP_001012338

Skin Melanoma;

Pancreas Ductal

Adenocarcinoma

2
F772L
Protein
0.1000
1.0000
1.0000
1.0000
0.9967
0.0695
Lung Adenocarcinoma;

Q773K
kinase

Lung Large Cell

NM_001012338

Neuroendocrine

NP_001012338

Carcinoma

5
T777M
Protein
0.2500
1.0000
0.4000
0.9836
0.9844
0.0904
Skin Melanoma;

E778K
kinase

Prostate Acinar

E778V

Adenocarcinoma;

NM_001012338

Soft Tissue

NP_001012338

Neuroblastoma

4
E781K
Protein
0.2000
1.0000
1.0000
1.0000
0.9952
0.0445
Lung Adenocarcinoma;

C782R
kinase

Breast Invasive Ductal

C782S

Carcinoma;

I783N

Pancreas Ductal

NM_001012338

Adenocarcinoma

NP_001012338

4
C782R
Protein
0.2000
1.0000
1.0000
1.0000
0.9952
0.0911
Lung Adenocarcinoma;

C782S
kinase

Head and Neck

I783N

Squamous Cell

T784S

Carcinoma;

NM_001012338

Pancreas Ductal

NP_001012338

Adenocarcinoma

8
G786C
Protein
0.4000
1.0000
1.0000
0.9180
0.9977
0.2156
Stomach

G786S
kinase

Adenocarcinoma;

R787C

Lung Adenocarcinoma;

R787H

Kidney Renal Cell

R787S

Carcinoma

NM_001012338

NP_001012338

4
L789F
Protein
0.2000
1.0000
0.2500
0.9672
0.7282
0.0059
Lung Squamous Cell

E790V
kinase

Carcinoma;

R791Q

Lung Adenocarcinoma;

R791W

Rectum

NM_001012338

Adenocarcinoma

NP_001012338

4
E790V
Protein
0.2000
1.0000
0.2500
0.9672
0.9404
0.0152
Lung Adenocarcinoma;

R791Q
kinase

Lung Squamous Cell

R791W

Carcinoma;

P792H

Rectum

NM_001012338

Adenocarcinoma

NP_001012338

6
R791Q
Protein
0.3000
1.0000
0.0000
0.7869
0.9603
0.0000
Lung Adenocarcinoma;

R791W
kinase

Colon

P792H

Adenocarcinoma;

R793L

Breast Ductal

R793Q

Carcinoma in Situ

NM_001012338

NP_001012338

3
P796L
Protein
0.1500
1.0000
1.0000
1.0000
0.9977
0.1497
Lung Adenocarcinoma;

P796S
kinase

Unknown Primary

NM_001012338

Malignant Neoplasm;

NP_001012338

Brain

Oligodendroglioma

5
D801N
Protein
0.2500
1.0000
1.0000
0.9672
0.9977
0.2111
Unknown Primary

NM_001012338
kinase

Melanoma;

NP_001012338

Head and Neck

Squamous Cell

Carcinoma;

Gallbladder

Adenocarcinoma

5
G805R
Protein
0.2500
1.0000
0.4000
1.0000
0.9967
0.0997
Unknown Primary

G805W
kinase

Melanoma;

C806S

Lung Adenocarcinoma;

W807G

Ovary Serous

NM_001012338

Carcinoma

NP_001012338

4
C806S
Protein
0.2000
1.0000
0.2500
1.0000
0.9964
0.0498
Lung Adenocarcinoma;

W807G
kinase

Ovary Serous

Q808H

Carcinoma;

NM_001012338

Stomach

NP_001012338

Adenocarcinoma

Diffuse Type

4
W807G
Protein
0.2000
1.0000
0.2500
1.0000
0.7716
0.0386
Lung Adenocarcinoma;

Q808H
kinase

Ovary Serous

R809W

Carcinoma;

NM_001012338

Stomach

NP_001012338

Adenocarcinoma

Diffuse Type

6
Q808H
Protein
0.3000
1.0000
0.5000
0.9836
0.8478
0.1103
Lung Adenocarcinoma;

R809W
kinase

Skin Melanoma;

E810K

Ovary Serous

NM_001012338

Carcinoma

NP_001012338

5
Q812H
Protein
0.2500
1.0000
0.4000
1.0000
0.9557
0.0936
Lung Non-Small Cell

Q813E
kinase

Lung Carcinoma;

Q813K

Lung Adenocarcinoma;

R814Q

Gallbladder

NM_001012338

Adenocarcinoma

NP_001012338

6
Q813E
Protein
0.3000
1.0000
0.5000
1.0000
0.8436
0.0799
Lung Non-Small Cell

Q813K
kinase

Lung Carcinoma;

R814Q

Lung Adenocarcinoma;

L815M

Kidney Chromophobe

NM_001012338

Carcinoma

NP_001012338

1
E819K
Protein
0.0500
1.0000
1.0000
1.0000
0.9977
0.0446
Skin Melanoma

NM_001012338
kinase

NP_001012338

2
K822R
Protein
0.1000
1.0000
1.0000
0.9508
0.8995
0.0000
Colon

NM_001012338
kinase

Adenocarcinoma;

NP_001012338

Unknown Primary

Adenocarcinoma

6
L824F
Protein
0.3000
1.0000
0.5000
0.9508
0.9136
0.0326
Unknown Primary

H825R
kinase

Melanoma;

H825Y

Lung Adenocarcinoma;

A826G

Colon Adenocarcinoma

A826S

A826V

NM_001012338

NP_001012338

7
H825R
Protein
0.3500
1.0000
0.1429
0.9508
0.9309
0.0203
Lung Adenocarcinoma;

H825Y
kinase

Unknown Primary

A826G

Melanoma;

A826S

Colon Adenocarcinoma

A826V

L827F

NM_001012338

NP_001012338

7
A826G
Protein
0.3500
1.0000
0.0000
0.9836
0.9822
0.0000
Lung Adenocarcinoma;

A826S
kinase

Ovary Serous

A826V

Carcinoma;

L827F

Skin Melanoma

G828E

G828W

NM_001012338

NP_001012338

1
A830D
Protein
0.0500
1.0000
1.0000
1.0000
0.9634
0.0048
Bone Marrow Multiple

NM_001012338
kinase

Myeloma

NP_001012338

6
P832A
Protein
0.3000
1.0000
0.5000
1.0000
0.9246
0.0438
Lung Adenocarcinoma;

P832R
kinase

Breast Carcinoma;

P832T

Skin Melanoma

I833V

Y834C

Y834N

NM_001012338

NP_001012338

2
D836E
Protein
0.1000
1.0000
1.0000
1.0000
0.9796
0.0980
Prostate Acinar

D836N
kinase

Adenocarcinoma;

NM_001012338

Lung Carcinosarcoma

NP_001012338

¹In some biopsy samples, mutation in the NTRK3 gene results in a TrkC protein lacking amino acids 548 to 562 in the wildtype TrkC protein (e.g., NP_001012338).

²Pediatric Cancer Gene Database, pedican.bioinfo-minzhao.org/gene_mutation.cgi?gene=4916, downloaded on May 31, 2016.

³Catalog of Somatic Mutations in Cancer (COSMIC) database, cancer.sanger.ac.uk/cosmic/mutation/overview?id=401588, downloaded on May 31, 2016.

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The point mutations observed in NTRK1, NTRK2, and NTRK3 appear to be more common in cancers that are associated with carcinogens known to generate point mutations (e.g., tobacco and UV exposure). As an example, the location of point mutations detected in NTRK3 are shown in FIG. 1 and the location of point mutations detected in NTRK3 have confirmed expression above background are shown in FIG. 2.

The data in Tables 1 and 2 show that a point mutation in NTRK2 that results in a substitution of the valine at amino acid position 689 in the TrkB protein with a different amino acid is present in cancer tissue. An examination of the crystal structure of TrkB suggests that the valine at amino acid position 689 of TrkB interacts with an asparagine at amino acid position 529 in the juxta-membrane domain, which may allow for the stabilization of the auto-inhibited conformation of the TrkB kinase (FIG. 3). When the valine at amino acid position 689 is mutated to a methionine, the large sidechain is predicted to clash with amino acids 746 to 748 in the C-terminal domain and result in a conformation change that may destabilize the auto-inhibited conformation of the TrkB kinase (FIG. 3).

The point mutations identified in the NTRK1, NTRK2, and NTRK3 genes may be used, for example, to select subjects for treatment of a Trk inhibitor, used to identify subjects that have an increased likelihood of having a positive response to treatment with a Trk inhibitor, used to determine a subject's risk of developing a cancer, and used to assist in the diagnosis of a cancer in a subject.

Other Embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

	Number	Date	Country
Parent	15579007	Dec 2017	US
Child	17533823		US

METHODS OF DIAGNOSING AND TREATING CANCER

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