High affinity nerve growth factor receptor (NTRK1) G595R mutant (TRKA G595R)

TRKA G595R is a specific solvent front mutation in the Tropomyosin receptor kinase A (TRKA) protein, encoded by the NTRK1 gene (UniProt P04629). This mutation is a well-characterized mechanism of acquired resistance in patients with NTRK fusion-positive cancers treated with first-generation TRK inhibitors like larotrectinib and entrectinib (Drilon et al., Cancer Discovery, 2017). The G595R substitution involves the replacement of a small glycine residue with a bulky arginine residue at the solvent front of the kinase domain. This structural change sterically hinders the binding of first-generation inhibitors while allowing the kinase to remain constitutively active (Russo et al., Cancer Discovery, 2016). The mutant protein continues to drive oncogenic cell proliferation and survival through downstream pathways such as MAPK/ERK and PI3K/AKT. Second-generation TRK inhibitors, including selitrectinib (LOXO-195) and repotrectinib (TPX-0005), have been specifically engineered to bind to the kinase domain despite the presence of the G595R mutation (Hyman et al., JCO, 2017; Drilon et al., JCO, 2020). These agents are designed to overcome the steric hindrance and restore therapeutic control over the disease. Consequently, TRKA G595R serves as a critical therapeutic target and biomarker for guiding subsequent lines of treatment in the setting of TRK-inhibitor resistance. Clinical management of patients with this mutation often involves the use of liquid biopsies or next-generation sequencing to detect the emergence of the G595R allele.

Other names

NTRK1 G595RTropomyosin receptor kinase A G595RTRK1 G595Rp140-TrkA G595RMTC G595R

ATP-competitive inhibition of the TRKA kinase domain to prevent autophosphorylation and downstream oncogenic signaling.