gsk-1363089 and Adenocarcinoma

Recent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset esophageal adenocarcinoma (EAC). We therefore studied the usefulness of combining HER2 and MET targeting by small-molecule inhibitors lapatinib and foretinib, respectively, both in in-vitro and in-vivo models of experimental EAC. We characterized MET and HER2 activation in a panel of human EAC cell lines, and the differential susceptibility of these EAC cell lines to single agent or combination of foretinib and lapatinib. We then explored the antitumor efficacy with survival advantage following foretinib and lapatinib monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. The OE33 EAC cell line with strong expression of phosphorylated both MET and HER2, demonstrated reduced sensitivity to foretinib and lapatinib when used as a single agent. The co-administration of foretinib and lapatinib effectively inhibited both MET and HER2 phosphorylation, enhanced inhibition of cell proliferation and xenograft tumor growth by inducing apoptosis, and significantly enhanced mouse overall survival, overcoming single agent resistance. In the OE19 EAC cell line with mainly HER2 phosphorylation, and the ESO51 EAC cell line with mainly MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined. These data suggest that combination therapy with foretinib and lapatinib should be tested as a treatment option for HER2 positive patients with MET-overexpressing EAC, and could be a novel treatment strategy for specific EAC patients.

Topics: Adenocarcinoma; Anilides; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carboplatin; Cell Line, Tumor; Esophageal Neoplasms; Female; Humans; Lapatinib; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasm Proteins; Paclitaxel; Peritoneal Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-met; Quinolines; Random Allocation; Receptor, ErbB-2; Tumor Burden; Xenograft Model Antitumor Assays

Recent genomic studies indicated that esophageal adenocarcinoma (EAC) is driven by amplification of c-MET or HER2 or both in a subset of patients. We studied the effect of MET targeting by the small molecule inhibitor foretinib in EAC cells and the interplay between MET and HER2 signaling.. We measured the expression levels and phosphorylation status of MET and HER2 proteins in EAC cell lines using Western blot analysis. The expression levels of MET and HER2 were manipulated by transfecting cells with specific siRNA or a plasmid expressing HER2. The small molecule inhibitors of c-MET and ERBB1/2 (foretinib and lapatinib, respectively) were tested for effect on growth, apoptosis, and downstream signaling pathways of EAC cells as single agents or in combination. The response to inhibitors was correlated to the levels of MET, HER2 expression, and amplification status.. Foretinib inhibits phosphorylation of MET, which correlated with reduced EAC cell growth and inhibition of AKT and ERK phosphorylation. Cell growth inhibition by foretinib is most profound in the ESO51 cell line, which has MET gene amplification and overexpression. Inhibition of MET signaling by foretinib or siRNA-specific knock down of MET expression induces apoptosis in ESO51 cells. Ectopic expression of HER2 reduces foretinib-mediated growth inhibition and downstream ERK phosphorylation in ESO51-HER2 cells. The EAC OE33 cell line, with amplification and overexpression of both MET and HER2, demonstrated reduced sensitivity to foretinib or lapatinib and had a transient effect on downstream inhibition of phosphorylated AKT and ERK (p-AKT, p-ERK). The coadministration of foretinib and lapatinib effectively blocked both MET and HER2 signaling through the p-AKT and p-ERK pathways, dramatically inhibited growth, and induced apoptosis to overcome single-agent resistance in OE33 cells.. The mechanism for foretinib growth inhibition in MET-amplified EAC tumor cells is demonstrated. The interplay of dual MET/HER2 overexpression in the AKT and ERK pathways for esophageal cancer is described. Therefore, combination therapy could be a novel strategy for EAC with amplification of both MET and HER2.

Topics: Adenocarcinoma; Anilides; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Proto-Oncogene Proteins c-met; Quinolines; Receptor, ErbB-2; Receptors, Vascular Endothelial Growth Factor; RNA, Neoplasm