NTRK Gene Fusions: A Driver of Oncogenesis1

TRK pathway signaling

Watch this video to learn how TRK fusion proteins activate signaling that may lead to uncontrolled growth in multiple tumors.

NTRK genetic rearrangements lead to constitutive activation of the TRK protein receptor1,2

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

How TRK fusion proteins occur2

Chart showing how TRK fusion proteins occur Chart showing how TRK fusion proteins occur

TRK fusion proteins are constitutively active and may promote oncogenic signaling that supports tumorigenesis1-3

  • Constitutive activation of TRK fusion proteins is caused by ligand-independent dimerization. This activation initiates downstream signaling pathways such as the AKT and MEK pathways1,2 
  • Cancers with kinase fusions characteristically depend on continued signaling from the oncogenic kinase for cell growth and survival3

The TRK signaling pathway1,2,4-6

TRK signaling pathway TRK signaling pathway


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.

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 States7

NTRK gene fusions are expressed in at least 25 types of cancer1,2,8

Acute myeloid leukemia
Appendiceal adenocarcinoma
Brain lower grade glioma
Colon adenocarcinoma
Colorectal cancer
Congenital fibrosarcomas
Congenital mesoblastic nephroma
Gastrointestinal stromal tumors
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
Secretory breast carcinoma
Skin cutaneous melanoma
Spitzoid neoplasms
Thyroid carcinoma


  1. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. PMID: 25527197
  2. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023. PMID: 27843590
  3. Shaw AT, Hsu PP, Awad MM, Engelman JA. Nat Rev Cancer. 2013;13(11):772-787. PMID: 24132104
  4. Khotskaya YB, Holla VR, Farago AF, et al. Pharmacol Ther. 2017;173:58-66. PMID: 28174090
  5. de Lartigue J. Oncology Live [serial online]. 2017;18(15). https://www.onclive.com/publications/oncology-live/2017/vol-18-no-15/trk-inhibitors-advance-rapidly-in-tumoragnostic-paradigm. Accessed September 4, 2018.
  6. Robbins HL, Hague A. Front Endocrinol (Lausanne). 2015;6:188. PMID: 26793165
  7. Kheder ES, Hong DS. Clin Cancer Res. 2018:1156. [Epub ahead of print.] PMID: 29986850
  8. Lange AM, Lo HW. Cancers (Basel). 2018;10(4). PMID: 29617282