Fibroblast growth factor receptor 1 (FGFR1) V561M (FGFR1 V561M)

Fibroblast growth factor receptor 1 (FGFR1) V561M is a specific point mutation located in the gatekeeper residue of the FGFR1 tyrosine kinase domain [Sohl et al., 2015]. This mutation involves the substitution of valine with methionine at position 561, which sterically hinders the binding of many conventional ATP-competitive kinase inhibitors, leading to drug resistance [Cowell et al., 2017]. Biologically, FGFR1 is a transmembrane receptor that, upon ligand binding, activates intracellular signaling cascades such as the RAS-MAPK and PI3K-AKT pathways to regulate cell growth, survival, and differentiation [UniProt P11362]. The V561M mutation is frequently identified as a secondary resistance mechanism in patients treated with FGFR inhibitors or as a primary driver in certain hematologic malignancies like the 8p11 myeloproliferative syndrome [Gozgit et al., 2012]. In the context of oncology, targeting this specific mutant requires next-generation or irreversible FGFR inhibitors, such as futibatinib or ponatinib, which can overcome the structural changes imposed by the methionine side chain [Soifer et al., 2022]. Monitoring for this mutation is crucial for clinical decision-making and managing therapeutic escape in FGFR-driven cancers [FDA, 2020].

Other names

FLT2CD331BFGFRCEKFGFBRHBGFRFGFR1 gatekeeper mutation

Inhibition of the tyrosine kinase activity of the FGFR1 protein, specifically targeting the ATP-binding site to block downstream signaling pathways such as RAS-MAPK, PI3K-AKT, and PLCγ [Sohl et al., 2015; UniProt P11362].