NTRK gene fusions cause the overexpression of TRK proteins¹

NTRK genes (NTRK1, NTRK2, or NTRK3 ) tend to fuse with housekeeping genes. Housekeeping genes are necessary for both cell maintenance and existence, so they are expressed in all cell types throughout an organism. Examples of partner housekeeping genes that fuse with NTRK genes include: TPM3, TRIM24, and ETV6.^2,11-14^9,10 Unless silenced, NTRK gene fusion leads to the expression of a chimeric protein, which retains the TRK kinase domain, but not the ligand-binding domain.¹ These TRK fusion proteins are continuously turned on due to the genetic alteration. Therefore, NTRK gene fusions can lead to the development of solid tumors in a variety of tissue types.^9,10

TRK fusion proteins are constitutively active^1,2

Fusions of NTRK genes have oncogenic potential regardless of fusion partner. Typically, dimerization of TRK proteins is mediated by the 5’ fusion partner, which allows the TRK portions of the proteins to autophosphorylate themselves independent of any regulation^1,2
As a result of this ligand-independent activation, TRK fusion proteins are constitutively active and propagate a constant signal cascade that causes cells to overproliferate and survive^1,2

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*TRK, tropomyosin receptor kinase.

^aNTRK, neurotrophic receptor tyrosine kinase.

References: 1. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023. 2. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. 3. Uren RT, Turnley AM. Regulation of neurotrophin receptor (Trk) signaling: suppressor of cytokine signaling 2 (SOCS2) is a new player [published online ahead of print May 14, 2017]. Front Mol Neurosci. 2014;7(39). doi:10.3389/fnmol.2014.00039. 4. Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM. Landscape of gene fusions in epithelial cancers: seq and ye shall find. Genome Med. 2015;7:129. doi:10.1186/s13073-015-0252-1. 5. Mertens F, Antonescu CR, Mitelman F. Gene fusions in soft tissue tumors: recurrent and overlapping pathogenic themes. Genes Chromosomes Cancer. 2016;55(4):291-310. 6. Latysheva NS, Oates ME, Maddox L, et al. Molecular principles of gene fusion mediated rewiring of protein interaction networks in cancer. Mol Cell. 2016;63(4):579-592. 7. Mahajan K, Mahajan NP. Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res. 2015;43(22):10588-10601. 8. Nanda N, Fennell T, Brandhuber B, Tuch BB, Low JA. Identification of tropomyosin kinase receptor (TRK) point mutations in cancer. Poster presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2015; Chicago, IL. Abstract 1553. 9. Yang L, Lee M-S, Lu H, et al. Analyzing somatic genome rearrangements in human cancers by using whole-exome sequencing. Am J Hum Genet. 2016;98(5):843-856. 10. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. doi:10.1038/ncomms5846. 11. Eisenberg E, Levanon EY. Human housekeeping genes, revisited. Trends Genet. 2013;29(10):569-574. 12. U.S. National Library of Medicine. Genetics Home Reference: TPM3 gene. https://ghr.nlm.nih.gov/gene/TPM3. Updated February 20, 2018. Accessed February 22, 2018. 13. U.S. National Library of Medicine. Genetics Home Reference: TRIM24 gene. https://ghr.nlm.nih.gov/gene/TRIM24. Updated February 20, 2018. Accessed February 22, 2018. 14. U.S. National Library of Medicine. Genetics Home Reference: ETV6 gene. https://ghr.nlm.nih.gov/gene/ETV6. Updated February 20, 2018. Accessed February 22, 2018.

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PATHOGENESIS OF TRK FUSION CANCER

NTRK gene fusions cause the overexpression of TRK proteins1