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

Abstract

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.

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity

“…Human hepatocellular carcinoma cancer cells express resistance to a MET inhibitor dependent on the phosphorylation status of FGFR It was recently reported that FGFR-expressing gastric cancer cells are sensitive to a MET inhibitor (22), implying that some association exists between MET and FGFR against the sensitivity to the MET inhibitor in a variety of cancer cells. We therefore investigated the dependence of the inhibitory effects of a MET inhibitor on the status of FGFR in human hepatocellular carcinoma cells.…”

“…Specifically, Kataoka and colleagues (22) reported that TKI appears to be more effective against human gastric cancer, by blocking inter-RTK signaling networks that depend on MET or FGFR2. Foretinib (GSK1363089), a multikinase inhibitor of MET and VEGFRs, shows different sensitivities that are dependent on FGFR expression (22). The FGFR inhibitor that has been most extensively studied in patients with HCC is brivanib, an ATP-competitive dual inhibitor of VEGFR and FGFR1-3 (24).…”

“…Although the biologic roles of the inter-RTK signaling networks are still unclear, FGFR and MET have been recently reported to interact with each other to promote cell growth or acquired resistance to specific inhibitors in gastric cancer cell lines (22). In the present study, we therefore evaluated the response of HCC cell lines and primary HCC cells to a MET inhibitor, to determine whether inhibition of the FGFR pathway can overcome the resistance to MET inhibitors.…”

cMET as a potential therapeutic target in gastric cancer (Review)

“…It can prevent tumor growth through a direct effect on tumor cell proliferation and through the inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors (68). In an in vitro study, foretinib appeared effective against gastric cancer cells harboring not only cMET but also FGFR2 amplification (69).…”

Exploitation of Aberrant Signalling Pathways as Useful Targets for Renal Clear Cell Carcinoma Therapy

“…Reports of a phase II trial with AMG 102 identified that although the drug brought about tumour burden reduction and long-term disease stability, it was unclear from the study whether this drug is capable of tumour growth inhibition in a histologically diverse population of patients with mRCC (Schoffski et al, 2010). Other drugs currently in development include foretinib (GSK1363089) an oral multi kinase inhibitor of MET and VEGFRs (Kataoka et al, 2011) (Yamazaki et al, 2011). The efficacy of these drugs have yet to be investigated in patients with RCC.…”