Tropomyosin receptor kinase family (Trk family) (Trk)

The Tropomyosin receptor kinase (Trk) family comprises three transmembrane receptor tyrosine kinases—TrkA, TrkB, and TrkC—which are essential for the development and maintenance of the central and peripheral nervous systems (UniProt P04629, Q16620, Q16288). These receptors are activated by specific neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), triggering signaling pathways like PI3K/Akt and MAPK that promote neuronal survival and synaptic plasticity (Huang & Reichardt, 2003). While physiologically vital, the Trk family is a significant driver of malignancy when NTRK genes undergo chromosomal rearrangements, leading to oncogenic fusion proteins (A. Russo et al., 2019). These fusions are found across a wide array of tumor types, including secretory breast carcinoma and infantile fibrosarcoma, making them ideal targets for precision medicine. Small-molecule inhibitors like larotrectinib and entrectinib have revolutionized treatment by providing potent, tumor-agnostic efficacy in patients with NTRK fusions (Drilon et al., 2018). Despite their success, clinicians must manage unique safety profiles, including neurotoxicity and weight gain, which stem from the inhibition of the receptors' normal functions in the brain.

Other names

NTRK familyNeurotrophic tyrosine kinase receptor familyTrkA/B/CTropomyosin-related kinaseHigh-affinity neurotrophin receptorsNTRK1NTRK2NTRK3

Competitive inhibition of the adenosine triphosphate (ATP) binding site within the intracellular tyrosine kinase domain of TrkA, TrkB, and TrkC, which prevents receptor autophosphorylation and the subsequent activation of downstream oncogenic signaling pathways such as MAPK/ERK, PI3K/Akt, and PLC-gamma (Vaishnavi et al., 2015; FDA Label: Vitrakvi).