The tropomyosin [TRK] gene fusion, originally described as an oddity in a colorectal cancer specimen, was the first non-RAS oncogene isolated from a human tumour. Its discovery enabled the identification of the NGF neurotropin family of signaling receptors TRKA, TRKB and TRKC encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes 1, 2, and 3, respectively [1,2].
Oncogenic gene fusions involving NTRK occur in numerous adult and paediatric tumour types [3-7], and have thus emerged as a promising therapeutic target across several tumour histologies. The estimated frequency of NTRK gene fusions varies between tumour types ranging from a prevalence of >90% in some rare cancers (secretory carcinoma of the breast and salivary glands and infantile fibrosarcoma) to <1% in more common cancer types  - (click here to learn more about the epidemiology of NTRK gene fusions). The protein product of NTRK gene fusions (referred to as a tropomyosin receptor kinase [TRK] fusion protein) is constitutively active and results in cell growth, proliferation and survival pathway activation [3, 5-7].
Timeline of key milestones in the NTRK gene fusion path from discovery to clinic (adapted from )
- Barbacid M. On the right TRK: from oncogene discovery to cancer therapeutics. Ann Oncol. 2019; 30(Suppi 8): viii3-viii4.
- Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 1986; 319(6056): 743–748.
- Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016; 1: e000023.
- Stransky N, Cerami E, Schalm S et al. The landscape of kinase fusions in cancer. Nat Commun 2014; 5: 4846.
- Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
- Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5: 25-34.
- Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018; 15(12):731-747.