The NTRK a gene family encodes the TRK* family of proteins1-3

The 3 NTRK genes, NTRK1, NTRK2, NTRK3 genes encodes the TRK family of proteins
The 3 NTRK genes, NTRK1, NTRK2, NTRK3 genes encodes the TRK family of proteins
The 3 NTRK genes, NTRK1, NTRK2, NTRK3 genes encodes the TRK family of proteins
  • The 3 NTRK genes (NTRK1, NTRK2, and NTRK3 ) each encode a separate TRK protein as TRKA, TRKB, and TRKC, respectively1,2
  • As transmembrane proteins, these kinases function by ligand-dependent transmission of extracellular signals to the nucleus, activating pathways that are involved in cell survival1-3
  • In their normal biological context, TRK proteins are expressed in neuronal cells and each plays a different and important role in nervous system development and maintenance1,2

NTRK gene fusion is caused by genomic rearrangement1,4,5

NTRK gene fusions are oncogenic drivers caused by genomic rearrangement
NTRK gene fusions are oncogenic drivers caused by genomic rearrangement
NTRK gene fusions are oncogenic drivers caused by genomic rearrangement
Image for illustrative purposes only.
  • In TRK fusion cancer, an NTRK gene fuses with another unrelated gene through nonhomologous end joining during DNA damage repair2,4,6,7
  • An NTRK gene fusion is different from an NTRK point mutation: NTRK gene fusions are often an oncogenic driver; NTRK point mutations are not believed to be1,8

NTRK gene fusions cause the overexpression of TRK proteins1

  • NTRK genes (NTRK1, NTRK2, or NTRK3 ) tend to fuse with housekeeping genes.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 active1,2

  • Fusions of NTRK genes have oncogenic potential regardless of fusion partner. Typically, dimerization of TRK fusion proteins is mediated by the 5ʹ fusion partner, which allows the TRK portions of the proteins to autophosphorylate themselves independent of any regulation1,2
  • 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 survive1,2
The more I know about the mechanism driving a cancer, the better I can care for my patients.
-Gerald Prager, MD

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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.