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

  • The 3 NTRK genes (NTRK1NTRK2, 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 cell growth, proliferation, and survival pathways, such as the MAPK/ERK and PI3K/AKT pathways1-3
  • 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

MAPK/ERK, mitogen-activated protein kinases/extracellular signal-regulated kinases; PI3K/AKT, phosphatidylinositol-3-kinase and protein kinase B.

References: 1. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. 2. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. 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. Front Mol Neurosci. 2014;7(39). doi:10.3389/fnmol.2014.00039.
 

NTRK gene fusion is caused by genomic rearrangement1-3

In TRK fusion cancer, an NTRK gene fuses with another unrelated gene through nonhomologous end joining during DNA damage repair.1,4-6

NTRK gene fusion is caused by genomic rearrangement

References: 1. 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. 2. 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. 3. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. 4. 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. 5. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34. 6. Mahajan K, Mahajan NP. Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res. 2015;43(22):10588-10601.

NTRK gene fusions cause the overexpression of TRK proteins1

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.1NTRK genes (NTRK1, NTRK2, or NTRK3 ) tend to fuse with housekeeping genes. Once fused, they 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. 2,3

References: 1. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. 2. 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. 3. Stransky N, Cerami E, Schalm S, Lim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. doi:10.1038/ncomms5846. 4. Eisenberg E, Levanon EY. Human housekeeping genes, revisited. Trends Genet. 2013;29(10):569-574. 5. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34. 6. 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. 7. 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. 8. 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.

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 5 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

 

TRK fusion proteins are constitutively active 

References: 1. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. 2. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.

 

 

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