Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks

• DOI: 10.1007/s10637-011-9699-0
• Publication Date: 2011-06-07T03:57:33Z
• Authors: Yu Kataoka; Toru Mukohara; Hideo Tomioka; Yohei Funakoshi; Naomi Kiyota; Yutaka Fujiwara; Masakazu Yashiro; Kosei Hirakawa; Midori Hirai; Hironobu Minami
• Keywords: 0301 basic medicine; Proto-Oncogene Proteins c-met; Models, Biological; Neoplasm Proteins; 3. Good health; ErbB Receptors; 03 medical and health sciences; Receptors, Vascular Endothelial Growth Factor; Drug Resistance, Neoplasm; Stomach Neoplasms; Cell Line, Tumor; Gene Knockdown Techniques; Quinolines; Humans; Anilides; Drug Screening Assays, Antitumor; Phosphorylation; Receptor, Fibroblast Growth Factor, Type 2; Protein Kinase Inhibitors; Cell Proliferation; Signal Transduction

To explore the mechanism of action of foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 μM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 μM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core.