Fibroblast growth factor receptor 1, 2, and 3 (FGFR1/2/3)

Fibroblast growth factor receptors 1, 2, and 3 (FGFR1/2/3) are a subgroup of the receptor tyrosine kinase (RTK) family that play critical roles in regulating cell proliferation, differentiation, and survival (Babina & Turner, 2017). These receptors are activated by the binding of fibroblast growth factor (FGF) ligands in the presence of heparin sulfate proteoglycans, leading to receptor dimerization and trans-autophosphorylation of the intracellular kinase domain (Ornitz & Itoh, 2015). This activation initiates several downstream signaling cascades, most notably the RAS-MAPK, PI3K-AKT, and PLCγ pathways, which are essential for embryonic development, tissue repair, and angiogenesis (Turner & Grose, 2010). In various human cancers, FGFR1/2/3 signaling is aberrantly activated through mechanisms such as gene amplification (e.g., FGFR1 in lung cancer), activating mutations (e.g., FGFR3 in bladder cancer), or chromosomal fusions (e.g., FGFR2 in cholangiocarcinoma) (Helsten et al., 2016). These alterations drive oncogenesis by promoting uncontrolled cell growth and resistance to apoptosis. Consequently, FGFR1/2/3 are major therapeutic targets for small-molecule tyrosine kinase inhibitors (TKIs) like erdafitinib and pemigatinib, which competitively inhibit ATP binding to the kinase domain (Xie et al., 2020). However, clinical use is often complicated by class-specific adverse effects, including hyperphosphatemia—resulting from the inhibition of FGF23-FGFR1 signaling in the kidney—and ocular toxicities such as serous retinopathy (Kuro-o, 2019; FDA, 2019).

Other names

CD331CD332CD333FGFR1FGFR2FGFR3Basic fibroblast growth factor receptor 1Fms-related tyrosine kinase 2Bacteria-expressed kinaseAchondroplasia receptorCEKBEKACH

ATP-competitive inhibition of the intracellular tyrosine kinase domain of FGFR1, FGFR2, and FGFR3, preventing receptor autophosphorylation and subsequent activation of downstream signaling pathways such as MAPK, PI3K/AKT, and PLCγ (Xie et al., 2020).