Fibroblast growth factor receptor 2, 3, and 4 (FGFR2-4)

The Fibroblast Growth Factor Receptors 2, 3, and 4 (FGFR2-4) are members of a family of four receptor tyrosine kinases (FGFR1-4) that regulate critical cellular processes such as proliferation, differentiation, and tissue repair (UniProt P21802, P22607, P22455). 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 (Nature Reviews Cancer, 2018). In oncology, FGFR2, FGFR3, and FGFR4 are frequently deregulated through gene fusions, mutations, or amplifications, serving as potent oncogenic drivers in various malignancies (NIH, 2023). For instance, FGFR2 fusions are characteristic of intrahepatic cholangiocarcinoma, while FGFR3 mutations and fusions are prevalent in urothelial carcinoma, and the FGF19-FGFR4 axis is implicated in hepatocellular carcinoma (PubMed, 2020). Therapeutic targeting of these receptors involves small-molecule tyrosine kinase inhibitors (TKIs) such as erdafitinib, pemigatinib, and futibatinib, which have received FDA approval for specific FGFR-altered cancers (FDA, 2019, 2020, 2022). Clinical management of these therapies is complicated by class-specific toxicities, including hyperphosphatemia, central serous retinopathy, and nail changes, as well as the development of resistance mutations in the kinase domain (StatPearls, 2023).

Other names

FGFR2FGFR3FGFR4CD332CD333CD334BEKACHJTK2FGFR2/3/4

Inhibition of the intracellular tyrosine kinase domain of fibroblast growth factor receptors 2, 3, and 4, which prevents receptor autophosphorylation and blocks downstream signaling through the MAPK, PI3K/AKT, and PLCγ pathways.