NTRK

NTRK refers to a family of human genes that encode neurotrophic receptor tyrosine kinases. The three members are NTRK1, NTRK2, and NTRK3, corresponding to the protein receptors TRKA, TRKB, and TRKC, respectively. These receptors are single-pass transmembrane proteins with an extracellular domain that binds neurotrophins, a transmembrane region, and an intracellular tyrosine kinase domain.

In the nervous system, Trk receptors mediate the effects of neurotrophins such as nerve growth factor (NGF) for TRKA, brain-derived neurotrophic factor (BDNF) and NT-4 for TRKB, and neurotrophin-3 (NT-3) for TRKC. Activation triggers signaling cascades including the MAPK/ERK, PI3K-AKT, and PLCγ pathways, promoting neuronal survival, differentiation, growth, and synaptic plasticity throughout development and in adulthood.

Genetically altered NTRK genes are clinically significant in cancer. NTRK gene fusions create constitutively active TRK fusion proteins that can drive tumor growth across many cancer types, sometimes irrespective of tissue origin. These fusions are relatively rare overall but occur in a wide spectrum of tumors, such as infantile fibrosarcoma, secretory breast carcinoma, congenital mesoblastic nephroma, and select gliomas and thyroid cancers. Detection typically involves next-generation sequencing of DNA or RNA, with fluorescence in situ hybridization or immunohistochemistry used in certain contexts as screening tools.

Therapies targeting TRK receptors have transformed management of NTRK fusion–positive cancers. TRK inhibitors such as larotrectinib and entrectinib have demonstrated tumor-agnostic efficacy, leading to approvals for tumors harboring NTRK fusions regardless of histology. Resistance can develop through additional mutations in the TRK kinase domain, prompting consideration of alternative therapies or clinical trials.