Tropomyosin receptor kinase and p75 neurotrophin receptor (Trk and p75NTR)

The neurotrophin receptor system consists of two distinct classes of cell surface receptors: the tropomyosin receptor kinases (TrkA, TrkB, and TrkC) and the p75 neurotrophin receptor (p75NTR) [Huang & Reichardt, 2003, Annu Rev Biochem]. Trk receptors are high-affinity receptor tyrosine kinases that mediate the prosurvival and growth-promoting effects of neurotrophins such as Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), and Neurotrophin-3 (NT-3) [Bothwell, 2014, Handb Exp Pharmacol]. In contrast, p75NTR is a member of the tumor necrosis factor receptor superfamily that binds all neurotrophins with low affinity but binds pro-neurotrophins with high affinity, often signaling for programmed cell death or growth cone collapse [Meeker & Williams, 2015, Prog Neurobiol]. These receptors play critical roles in the development, maintenance, and plasticity of the nervous system, and their dysfunction is linked to neurodegenerative diseases, chronic pain, and various malignancies [Cocco et al., 2018, Nat Rev Clin Oncol]. In oncology, chromosomal rearrangements leading to NTRK gene fusions result in constitutively active Trk fusion proteins, which serve as primary oncogenic drivers across a wide range of adult and pediatric tumors [Drilon et al., 2018, NEJM]. Therapeutic targeting of this system includes the use of highly selective Trk inhibitors like larotrectinib and entrectinib for cancer, as well as the development of p75NTR modulators and anti-NGF antibodies for neurological and pain disorders [Lieu et al., 2022, J Hematol Oncol]. Safety considerations for these therapies often involve neurological side effects, such as dizziness and cognitive changes, reflecting the receptors' fundamental roles in the central and peripheral nervous systems [Lieu et al., 2022, J Hematol Oncol].

Other names

Nerve growth factor receptorNGFRTrkATrkBTrkCp75CD271TNFRSF16NTRK1NTRK2NTRK3Neurotrophin receptor

Inhibition of the intracellular tyrosine kinase domain of Trk receptors (TrkA/B/C) to prevent downstream oncogenic signaling; sequestration of neurotrophin ligands (e.g., NGF) to prevent activation of both Trk and p75NTR; and small-molecule modulation of p75NTR to influence neuronal survival and death pathways.