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NTRK Gene Fusions: A Driver of Oncogenesis1

TRK pathway signaling may drive tumor survival and growth2

  • In normal healthy tissue, the TRK pathway plays a role in the development of the central and peripheral nervous systems and pain sensation3
  • In a wide range of cancer types NTRK gene fusions can occur, leading to genetically altered TRK receptor proteins that may drive signaling pathways involved in cell proliferation, survival, invasion, and angiogenesis2

NTRK genetic rearrangements lead to constitutive activation of the TRK protein receptor2

  • Members of the TRK protein family of receptors, TRKA, TRKB, and TRKC, are encoded by the 3 NTRK genes, NTRK1, NTRK2, and NTRK3, respectively1
  • Genomic rearrangements in the NTRK genes lead to TRK fusion proteins2

How TRK fusion proteins occur2

Chart showing how NTRK gene fusions occur

TRK fusion proteins are constitutively active and may promote oncogenic signaling that supports tumorigenesis1

  • Constitutive activation of TRK fusion proteins is caused by ligand-independent dimerization. This activation initiates downstream signaling pathways such as the AKT and MEK pathways1
  • Cancers with kinase fusions characteristically depend on continued signaling from the oncogenic kinase for cell growth and survival4

The TRK signaling pathway2

NTRK signaling pathway

NTRK gene fusions are a primary oncogenic driver of various cancers1

  • TRK receptor signaling has been shown to promote tumorigenesis, cell survival and metastasis in several different tumor types1
  • The prevalence of NTRK gene fusions varies across tumor types and adult and pediatric cancers1
  • The annual incidence of NTRK gene fusion-driven tumors is estimated to be 1500–5000 cases in the United States5

NTRK gene fusion variants are expressed in at least 25 types of cancer2

Acute myeloid leukemia
Appendiceal adenocarcinoma
Astrocytoma
Brain lower grade glioma
Breast
Colon adenocarcinoma
Colorectal cancer
Congenital fibrosarcomas
Congenital mesoblastic nephroma
Gastrointestinal stromal tumors
Glioblastoma
Head and neck squamous cell carcinoma
Intrahepatic cholangiocarcinoma
Large cell neuroendocrine tumor
Lung adenocarcinoma
Mammary analogue secretory carcinoma
Non-small cell lung cancer
Pancreatic cancer
Papillary thyroid cancer
Pediatric gliomas
Ph-like acute lymphoblastic leukemia
Sarcoma
Secretory breast carcinoma
Skin cutaneous melanoma
Spitzoid neoplasms
Thyroid carcinoma

NTRK Gene Fusion proposed MOA

Watch how NTRK gene fusions drive oncogenesis.

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    F
    Fluorescence in situ hybridization (FISH)

    Cytogenetic technique used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence complementarity.

    Fusion Protein

    A protein created by joining different genes that are transcribed and translated as a single unit.

    I
    Immunohistochemistry (IHC)

    Uses antibodies to detect the target protein on tissue sections.

    T
    TRK

    Tropomyosin receptor kinase. Members of the TRK protein family of receptors, TRKA, TRKB, and TRKC, are encoded by the 3 NTRK genes, NTRK1, NTRK2, and NTRK3, respectively.

AKT=v-akt murine thymoma viral oncogene homologue; DAG=diacyl-glycerol; ERK=extracellular signal-regulated kinase; MEK=mitogen-activated protein kinase; mTOR=mammalian target of rapamycin; NTRK=neurotrophic tyrosine receptor kinase;
PI3K=phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC=protein kinase C; PLCy=phospholipase C gamma; RAF=rapidly accelerated fibrosarcoma kinase; Ras=rat sarcoma kinase; TRK=tropomyosin receptor kinase.

    • Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. PMID: 25527197

      Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. PMID: 25527197

    • Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023. PMID: 27843590

      Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023. PMID: 27843590

    • Chong CR, Bahcall M, Capelletti M, et al. Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer. Clin Cancer Res. 2017;23(1):204-213. PMID: 27370605

      Chong CR, Bahcall M, Capelletti M, et al. Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer. Clin Cancer Res. 2017;23(1):204-213. PMID: 27370605

    • Shaw AT, Hsu PP, Awad MM, Engelman JA. Nat Rev Cancer. 2013;13(11):772-787. PMID: 24132104

      Shaw AT, Hsu PP, Awad MM, Engelman JA. Nat Rev Cancer. 2013;13(11):772-787. PMID: 24132104

    • Kheder ES, Hong DS. Clin Cancer Res. 2018:1156. [Epub ahead of print.] PMID: 29986850

      Kheder ES, Hong DS. Clin Cancer Res. 2018:1156. [Epub ahead of print.] PMID: 29986850

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