NTRK1

NTRK1, or neurotrophic receptor tyrosine kinase 1, is a gene that encodes the receptor protein TrkA, a member of the Trk family of receptor tyrosine kinases. TrkA is a high-affinity receptor for nerve growth factor (NGF). The protein has an extracellular domain with immunoglobulin-like motifs, a single pass transmembrane segment, and an intracellular tyrosine kinase domain. Upon NGF binding, TrkA dimerizes and undergoes autophosphorylation, initiating signaling cascades.

During development, NTRK1 is highly expressed in sympathetic and sensory neurons and continues to contribute to the maintenance and plasticity of certain neuronal populations in adulthood. Activation of TrkA triggers signaling pathways such as MAPK/ERK, PI3K/AKT, and PLCγ, promoting neuronal survival, differentiation, axonal growth, and synaptic modulation, including pain signaling in nociceptive pathways.

Clinically, loss-of-function mutations in NTRK1 cause congenital insensitivity to pain with anhidrosis (CIPA), a hereditary sensory and autonomic neuropathy characterized by absent pain perception, impaired sweating, and thermoregulatory instability in early life. In oncogenesis, NTRK1 can be rearranged into fusion genes with various partners, producing constitutively active TrkA kinases that drive tumor growth in a subset of cancers, including certain thyroid and other solid tumors. These NTRK1 fusions are targeted by TRK inhibitors such as larotrectinib and entrectinib, which can yield tumor-agnostic responses across multiple cancer types. Resistance may arise through acquired mutations in the kinase domain.

Diagnostic testing for NTRK1 fusions typically involves molecular profiling of tumors, using methods such as next-generation sequencing, fluorescence in situ hybridization, or immunohistochemistry. The evaluation of TrkA signaling remains an area of active research, with ongoing exploration of therapeutic strategies for pain disorders and TRK fusion–driven cancers.