Abstract A238: The effects of foretinib on MET phosphorylation, gene expression, cell proliferation and tumor growth in MET-amplified tumor cells in vitro and in vivo

Abstract

Abstract The MET receptor tyrosine kinase (RTK) is frequently deregulated in many types of cancer and is a promising target for cancer drug development. Foretinib is a multikinase inhibitor with potent activity against MET and is currently in phase II clinical trials. In these studies, we determined the anti-tumor activity of foretinib in MET-amplified tumor cells and the MKN45 gastric xenograft tumor model in nude mice. We also measured the effect of foretinib on MET phosphorylation by immunoprecipitation and western blot and evaluated gene expression by Affymetrix microarrays in these models. In vitro foretinib demonstrated the most potent cell growth inhibitory activity in MET-amplified tumor cell lines MKN45 (IC50 = 9 ± 2 nM), HS746T (IC50 = 8 ± 2 nM), SNU5 (IC50 = 2 ± 0.2 nM) and NCI-H1993 (IC50 = 69 ± 5 nM). Foretinib inhibited the phosphorylation of MET, suppressed the phosphorylation of AKT and ERK, and reduced the expression of cyclin D1 in a dose dependent manner in these cells. Furthermore, foretinib given orally showed durable and near complete inhibition of MET phosphorylation (>90%) and dose dependent anti-tumor activity against MKN45 MET-amplified gastric xenograft tumors in nude mice. Tumor stasis and significant tumor growth delay were observed for foretinib dosed at 10 mg/kg and PF-02341066, a MET selective inhibitor, dosed at 50 mg/kg in the same study. In addition, foretinib or PF-02341066 showed similar gene alterations on both MKN45 cells and xenograft tumors. These genes are involved in RTK cross-talk and MET signaling pathways (e.g., HER2, HER3, MET, PIK3IP1, DUSP4, DUSP6), cell motility (e.g., CDH1, TIMP2, CLDN3, MMP1), cell proliferation (e.g., CCND1, TP53INP1, TYMS, CCNB1) and apoptosis (e.g., TNFSF10, CASP8). These results demonstrate that foretinib is a potent MET inhibitor with associated changes in gene expression which correlate with anti-tumor activity in MET-amplified tumor cells both in vitro and in vivo. This gene signature warrants further investigation for its relevance as a MET-inhibitor mediated pharmacodynamic marker. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A238.