Fibroblast growth factor receptor 2 N550H (FGFR2 N550H)

Fibroblast growth factor receptor 2 (FGFR2) N550H is a specific gain-of-function mutation located within the kinase domain of the FGFR2 protein, specifically affecting the molecular brake region that normally maintains the kinase in an inactive state (Source: UniProt P21802). This mutation leads to constitutive, ligand-independent activation of the receptor, driving uncontrolled cellular proliferation and survival through the MAPK and PI3K/AKT signaling pathways. Clinically, the N550H variant is most frequently observed in endometrial carcinomas and is also identified in a subset of cholangiocarcinomas and gastric cancers (Source: MyCancerGenome). While FGFR2 is a well-established therapeutic target, the N550H mutation is significant because it can confer varying degrees of sensitivity or resistance to different classes of FGFR inhibitors. For instance, while it may show reduced sensitivity to some early-generation ATP-competitive inhibitors, it remains a primary target for potent pan-FGFR inhibitors like erdafitinib and next-generation covalent inhibitors like futibatinib (Source: PubMed PMID: 28801538). Understanding the presence of the N550H mutation is essential for precision medicine approaches in oncology to select the most effective tyrosine kinase inhibitor for the patient.

Other names

FGFR2 N550H mutantFibroblast growth factor receptor 2 (N550H)CD332 N550HBEK N550HProtein tyrosine kinase receptor N550H

Inhibition of the tyrosine kinase activity of the mutated FGFR2 protein by competing for the ATP-binding site or through covalent binding, thereby blocking downstream oncogenic signaling pathways such as MAPK/ERK, PI3K/AKT, and STAT (Source: PubMed PMID: 33076116).