Fibroblast growth factor receptor 3 (FGFR3) K650M (FGFR3 K650M)

Fibroblast growth factor receptor 3 (FGFR3) is a transmembrane receptor tyrosine kinase that plays a pivotal role in regulating chondrocyte proliferation and bone development (UniProt P22607). The K650M mutation, located in the activation loop of the kinase domain, results in a constitutively active receptor that signals independently of ligand binding (Bellus et al., 1999, Am J Med Genet). This specific gain-of-function mutation is the genetic hallmark of SADDAN (Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans) syndrome and is also found as a somatic driver in various malignancies, including urothelial carcinoma and multiple myeloma (Chesi et al., 1997, Nature Genetics). In the context of cancer, the hyperactive FGFR3 K650M protein triggers downstream pathways like RAS-MAPK and PI3K-AKT, promoting tumor cell survival and proliferation. Therapeutic intervention typically involves small-molecule inhibitors, such as erdafitinib, designed to block the kinase activity of the receptor (FDA, Balversa Label). However, clinical use of these inhibitors is often limited by class-specific toxicities, most notably hyperphosphatemia, and the potential for acquired resistance through secondary mutations.

Other names

CD333ACHCEK2JTK4FGFR-3Fibroblast growth factor receptor 3 (K650M mutation)

ATP-competitive inhibition of the FGFR3 tyrosine kinase domain, which prevents receptor autophosphorylation and blocks downstream oncogenic signaling pathways such as RAS-MAPK and PI3K-AKT.