Fibroblast growth factor receptor 3 (FGFR3) (K650E mutation) (FGFR3-K650E)

FGFR3-K650E is a specific gain-of-function mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3), a transmembrane receptor tyrosine kinase [1, 4]. This mutation is located in the activation loop of the kinase domain and results in constitutive, ligand-independent activation of the receptor [1, 2]. In embryonic development, the germline K650E mutation is the primary cause of Thanatophoric Dysplasia Type II (TDII), a lethal skeletal disorder characterized by severe limb shortening and cloverleaf skull [2, 6]. Somatically, FGFR3-K650E acts as an oncogenic driver in various malignancies, including urothelial carcinoma and multiple myeloma, where it stimulates downstream signaling through the MAPK/ERK and PI3K/AKT pathways to promote cell proliferation and survival [4, 7]. Therapeutic interventions primarily utilize small-molecule tyrosine kinase inhibitors (TKIs) such as erdafitinib and infigratinib, which compete with ATP to inhibit the receptor's catalytic activity [4, 11, 12]. While these inhibitors show clinical efficacy, their use is associated with specific toxicities like hyperphosphatemia and ocular issues, and patients often develop resistance over time [10, 15, 17].

Other names

CD333ACHCEK2JTK4FGFR3-K650EFibroblast growth factor receptor 3 K650ELys650Glu

Tyrosine kinase inhibition