Fibroblast growth factor receptor family (FGFR) (FGFR)

The Fibroblast Growth Factor Receptor (FGFR) family consists of four highly conserved transmembrane receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4) that regulate essential cellular processes including proliferation, differentiation, and survival [1.1.1, 1.4.1]. These receptors are activated by the binding of fibroblast growth factor (FGF) ligands, which triggers receptor dimerization and autophosphorylation of the intracellular kinase domain, subsequently activating the RAS-MAPK, PI3K-AKT, and PLCγ signaling pathways [1.2.1, 1.3.1]. Dysregulation of FGFR signaling, particularly through genetic alterations in FGFR2 and FGFR3 such as fusions, mutations, and amplifications, is a key oncogenic driver in various cancers, including urothelial carcinoma, cholangiocarcinoma, and gastric cancer [1.2.2, 1.3.3]. In addition to its role in oncology, FGFR3 is a critical regulator of bone growth, and its activating mutations are responsible for skeletal dysplasias like achondroplasia [1.1.2, 1.4.1]. Therapeutic targeting of the FGFR family has led to the approval of several selective tyrosine kinase inhibitors, such as erdafitinib and pemigatinib, for patients harboring specific FGFR alterations [1.2.3, 1.3.3]. However, clinical use is often limited by class-specific toxicities, most notably hyperphosphatemia and ocular effects like central serous retinopathy, as well as the eventual emergence of resistance mutations [1.3.3, 1.4.1].

Other names

FGFR1FGFR2FGFR3FGFR4CD331CD332CD333CD334BFGFRCEKFLGFLT2HBGFR

ATP-competitive inhibition of the intracellular tyrosine kinase domain, preventing receptor autophosphorylation and downstream signaling through the RAS-MAPK, PI3K-AKT, and PLCγ pathways.