Tropomyosin receptor kinase A and Tropomyosin receptor kinase B (TrkA/TrkB)

Tropomyosin receptor kinase A (TrkA) and Tropomyosin receptor kinase B (TrkB) are high-affinity receptor tyrosine kinases encoded by the NTRK1 and NTRK2 genes, respectively [9, 15]. They serve as the primary receptors for neurotrophins, with TrkA binding Nerve Growth Factor (NGF) and TrkB binding Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-4 (NT-4) [9, 12]. These receptors are essential for the development, survival, and functional maintenance of the central and peripheral nervous systems, regulating processes such as neuronal differentiation, synaptic plasticity, and neurogenesis [7, 15]. In oncology, chromosomal fusions involving NTRK1 or NTRK2 lead to constitutively active kinase signaling, driving a variety of solid tumors in both adults and children [8, 14]. Conversely, reduced TrkB signaling is implicated in neurodegenerative diseases like Alzheimer's and psychiatric conditions such as depression [1, 13]. Therapeutic interventions include pan-TRK inhibitors like larotrectinib and entrectinib for fusion-positive cancers, as well as TrkB agonists and allosteric modulators (including certain antidepressants) for neurological and psychiatric disorders [2, 6, 8].

Other names

NTRK1NTRK2Neurotrophic receptor tyrosine kinase 1Neurotrophic receptor tyrosine kinase 2High affinity nerve growth factor receptorBDNF/NT-3 growth factors receptorTrk-ATrk-B

Drugs targeting TrkA and TrkB primarily act through two distinct mechanisms: competitive inhibition of the ATP-binding site in the kinase domain to block oncogenic signaling in cancers harboring NTRK fusions, or allosteric potentiation and direct agonism of the receptors to enhance neurotrophic signaling and synaptic plasticity in neurological and psychiatric disorders.