Neurotrophic receptor tyrosine kinase 3 (NTRK3) G623R (TRKC G623R)

Neurotrophic receptor tyrosine kinase 3 (NTRK3) G623R is a clinically significant acquired resistance mutation found in patients with TRK fusion-positive cancers treated with first-generation TRK inhibitors [Cocco et al., 2018]. The mutation involves a substitution of glycine with arginine at the solvent front of the kinase domain's ATP-binding pocket [Drilon et al., 2018]. This change creates steric hindrance that prevents first-generation inhibitors like larotrectinib and entrectinib from binding effectively, leading to disease progression [Amatu et al., 2019]. TRKC G623R is the most common mechanism of acquired resistance in NTRK3-fusion-positive tumors [Drilon, 2019]. To address this, next-generation macrocyclic or small-molecule inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed to fit within the modified binding pocket [Drilon et al., 2020]. These agents are currently used or being investigated to restore kinase inhibition and provide therapeutic benefit to patients who have failed initial TRK-targeted therapy [NCCN Guidelines, 2023].

Other names

NTRK3 G623RTropomyosin receptor kinase C G623RTRKC solvent front mutationp.Gly623Argp.G623R

ATP-competitive inhibition of the NTRK3 kinase domain; next-generation inhibitors are specifically designed to bypass steric hindrance at the solvent front caused by the bulky arginine side chain [Drilon et al., 2018].