Neurotrophic receptor tyrosine kinase fusion protein (NTRK fusion protein) (NTRK fusion)

Neurotrophic receptor tyrosine kinase (NTRK) fusion proteins are oncogenic drivers resulting from chromosomal rearrangements that fuse the 3' kinase domain of NTRK1, NTRK2, or NTRK3 with the 5' end of various partner genes (Amodio et al., 2020, Nature Reviews Clinical Oncology). Under normal physiological conditions, the wild-type TRK receptors (TrkA, TrkB, and TrkC) are activated by neurotrophins to regulate neuronal growth, differentiation, and survival (Huang & Reichardt, 2003, Annual Review of Neuroscience). However, the resulting fusion proteins are constitutively active and ligand-independent, leading to uncontrolled signaling through the MAPK, PI3K, and PLC-gamma pathways, which promotes cell proliferation and survival (Cocco et al., 2018, Nature Medicine). These fusions are found in a wide range of adult and pediatric solid tumors, including rare types like infantile fibrosarcoma and common types like lung or colorectal cancer (Drilon et al., 2018, New England Journal of Medicine). Therapeutic targeting of these proteins with selective tyrosine kinase inhibitors (TKIs) such as larotrectinib and entrectinib has shown high efficacy regardless of the tumor's tissue of origin, marking a significant milestone in tumor-agnostic precision medicine (Doebele et al., 2020, Lancet Oncology). Despite their success, clinical challenges include the development of acquired resistance mutations in the kinase domain and off-target neurological side effects due to the essential role of TRK receptors in the central nervous system (NCI, 2023).

Other names

TRK fusion proteinTropomyosin receptor kinase fusionNTRK1/2/3 fusionOncogenic NTRK fusionTrk receptor fusion

Selective inhibition of the tropomyosin receptor kinase (TRK) family (TrkA, TrkB, and TrkC) to block downstream oncogenic signaling pathways such as MAPK, PI3K, and PLC-gamma that are constitutively activated by the fusion event.