Neurotrophic tyrosine receptor kinase family (NTRK)

The Neurotrophic Tyrosine Receptor Kinase (NTRK) family consists of three transmembrane proteins—TrkA, TrkB, and TrkC—encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively (1, 2, 10). These receptors are primarily expressed in the nervous system, where they play critical roles in neuronal development, differentiation, and survival by binding to neurotrophins like NGF, BDNF, and NT-3 (3, 12, 15). In various cancers, chromosomal rearrangements can lead to NTRK gene fusions, resulting in constitutively active chimeric TRK proteins that drive oncogenesis (1, 4, 18). These fusions are found in a wide range of adult and pediatric solid tumors, making them a key target for tumor-agnostic therapies (1, 8, 18). Targeted TRK inhibitors, such as larotrectinib and entrectinib, have shown high efficacy in treating patients with these genomic alterations (4, 12, 16). However, the development of acquired resistance mutations and the management of neurological side effects remain significant clinical challenges (4, 16, 17).

Other names

Trk familyTropomyosin receptor kinase familyNTRK1NTRK2NTRK3TrkATrkBTrkC

Inhibition of the kinase activity of constitutively active TRK fusion proteins by binding to the ATP-binding pocket of the kinase domain.