Fibroblast growth factor receptor 2 IIIb isoform (FGFR2b) (FGFR2b)

Fibroblast growth factor receptor 2 IIIb isoform (FGFR2b) is a splice variant of the FGFR2 receptor tyrosine kinase, characterized by the inclusion of exon 8 (IIIb) in the third immunoglobulin-like domain of its extracellular region (UniProt: P21802). This specific isoform is predominantly expressed on epithelial cells and serves as the primary receptor for ligands such as FGF7, FGF10, and FGF22, which are secreted by neighboring mesenchymal cells (PubMed: 21673111). In various malignancies, particularly gastric and gastroesophageal junction cancers, FGFR2b is frequently overexpressed or the FGFR2 gene is amplified, leading to constitutive signaling that promotes tumor cell proliferation, survival, and invasion (PubMed: 34755117). Therapeutic strategies targeting the extracellular domain of FGFR2b, such as the monoclonal antibody bemarituzumab (FPA144), aim to inhibit ligand-mediated activation and induce immune-mediated tumor cell death via antibody-dependent cellular cytotoxicity (PubMed: 32605917). Unlike pan-FGFR small molecule inhibitors that target the intracellular kinase domain and often cause systemic toxicities like hyperphosphatemia, antibodies targeting the FGFR2b extracellular domain offer a more selective approach with a distinct safety profile (PubMed: 34755117). Clinical development has focused on patient populations identified through immunohistochemistry or genomic testing to ensure high expression of the target isoform (NCT03694522).

Other names

Keratinocyte growth factor receptorKGFRCD332FGFR2-IIIbBacteria-expressed kinaseBEK

The primary mechanism of action for drugs targeting the FGFR2b extracellular domain involves the competitive inhibition of ligand binding (specifically FGF7, FGF10, and FGF22), which prevents receptor dimerization and the subsequent activation of downstream signaling pathways like MAPK/ERK and PI3K/AKT (PubMed: 32605917). Additionally, engineered antibodies such as bemarituzumab are designed to enhance antibody-dependent cellular cytotoxicity (ADCC), recruiting natural killer cells to the tumor site to facilitate direct cell lysis (PubMed: 34755117).