Tropomyosin receptor kinase A, B, and C (NTRK1, NTRK2, and NTRK3) (TRK)

The Tropomyosin receptor kinase (TRK) family, comprising TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3), consists of transmembrane receptor tyrosine kinases essential for the development and maintenance of the central and peripheral nervous systems (UniProt: P04629, Q16620, Q16288). These receptors are activated by neurotrophins, triggering signaling pathways that regulate cell survival, differentiation, and synaptic plasticity. In various cancers, chromosomal rearrangements result in NTRK gene fusions, leading to the expression of chimeric TRK proteins with constitutively active kinase domains that drive tumor growth regardless of tissue origin (Nature Reviews Clinical Oncology, 2018). While first-generation TRK inhibitors like larotrectinib and entrectinib show high efficacy in fusion-positive tumors, clinical resistance often emerges through specific kinase domain mutations, such as solvent front (e.g., TRKA G595R) or gatekeeper mutations (Cancer Discovery, 2018). Next-generation inhibitors like repotrectinib and selitrectinib are specifically designed to bind effectively to these resistance mutants while maintaining potency against wild-type and fusion proteins. Consequently, this target group represents a critical focus for tissue-agnostic precision oncology, requiring sophisticated molecular diagnostics for patient selection and monitoring.

Other names

Neurotrophic tyrosine kinase receptor type 1Neurotrophic tyrosine kinase receptor type 2Neurotrophic tyrosine kinase receptor type 3NTRK1NTRK2NTRK3TrkATrkBTrkCNTRK fusionsTRK resistance mutants

Small molecule inhibition of the adenosine triphosphate (ATP)-binding site of the tropomyosin receptor kinase (TRK) family, preventing autophosphorylation and downstream signaling cascades such as MAPK, PI3K, and PLC-gamma (PubMed: 30107174).