Ther GP 3 Ant

nloaded regulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human s. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its s, mutations, and receptor amplification, has been found in a variety of human tumors. We generated lonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 origenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. ore, we used an FGFR2-IIIb–specific antibody, GP369, to investigate the importance of FGFR2 signaling o and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb wnstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice cantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findupport the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways ed in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified involv FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies. Cancer Res; 70(19); 7630–9. ©2010 AACR.