Neurotrophic tyrosine receptor kinase (NTRK) (NTRK)

The neurotrophic tyrosine receptor kinase (NTRK) family consists of three transmembrane proteins—NTRK1, NTRK2, and NTRK3—which encode the TrkA, TrkB, and TrkC receptors, respectively (UniProt P04629, Q16620, Q16288). These receptors play a fundamental role in the development and maintenance of the central and peripheral nervous systems by binding neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) (Amatu et al., 2019). Upon ligand binding, NTRK receptors undergo dimerization and autophosphorylation, activating signaling cascades such as the MAPK/ERK, PI3K/Akt, and PLCγ pathways that promote cell survival and differentiation (Cocco et al., 2018). In oncology, chromosomal rearrangements leading to NTRK gene fusions result in the constitutive activation of these kinases, driving oncogenesis across a wide variety of adult and pediatric solid tumors (NCI, 2023). Consequently, the NTRK family has become a significant therapeutic target for tumor-agnostic precision medicine. Selective TRK inhibitors, such as larotrectinib and entrectinib, have demonstrated high efficacy in patients harboring these fusions (FDA, 2018). However, acquired resistance mutations in the kinase domain, such as solvent front mutations, remain a clinical challenge (Drilon et al., 2018). Beyond cancer, the NTRK pathway is investigated for its role in pain management and neurodegenerative conditions.

Other names

Tropomyosin receptor kinaseTrk receptor familyNTRK1/2/3TrkA/B/CTrk family

Small molecule inhibition of the kinase domain of NTRK proteins, preventing downstream signaling pathways like MAPK, PI3K, and PLC-gamma (Cocco et al., 2018).