Abstract 4826: Synergistic effects of foretinib with lapatinib in MET and HER2 co-activated experimental esophageal adenocarcinoma
Authors: Hassan Md Sazzad , Williams Fiona , Awasthi Niranjan , Schwarz Margaret A. , Schwarz Roderich E. , Holzen Urs von 
Published: August 2018

Abstract
Introduction: 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 foretinib and lapatinib both in-vitro and in-vivo models of experimental EAC.
Methods: In this study we first characterized MET and HER2 activation in a panel of human EAC cell lines and the differential susceptibility of these EAC cell lines to single agents or combinations of foretinib, a multi-kinase MET inhibitor, with HER2 targeted agent lapatinib. We evaluated the levels of phosphorylation status of MET and HER2 proteins using western blot in EAC cell lines. Foretinib and lapatinib, as single agent or in combination were tested for effect on cell growth as detected by WST-1 assay and on cell apoptosis as detected by western blot of cleavage of caspase 3 and poly ADP ribose polymerase (PARP). In addition, we explored the antitumor efficacy with survival advantage following foretinib and lapatinib mono and combination therapies for two weeks in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC.
Results: The OE33 EAC cell line with phosphorylation of 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, synergistically inhibited cell growth and induced apoptosis, overcoming single agent resistance. In the OE19 EAC cell line with only HER2 phosphorylation and the ESO51 EAC cell line with only MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent foretinib and lapatinib, respectively, with lack of enhanced growth inhibition when the two drugs were combined. Foretinib in combination with lapatinib treatment resulted in significantly higher antitumor efficacy and survival benefit compared with foretinib or lapatinib treatment alone. In subcutaneous xenografts using OE33 cells, average net tumor growth after two weeks in different therapy groups was 247.83 mm3 in control, 216.71 mm3 after foretinib (p=0.49), 239.68 mm3 after lapatinib (p=0.74), and 108.06 mm3 after foretinib plus lapatinib (p=0.0011). In the OE33 survival model there was a significant increase in median animal survival after two weeks foretinib plus lapatinib treatment (71 days) compared to control (60 days, p=0.0021), to foretinib therapy (63 days, p=0.0019) or to lapatinib (61 days, p=0.0019) therapy.
Conclusion: 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. Therefore, this combination therapy could be a novel treatment strategy for EAC with MET and HER co-activation.
Citation Format: Md Sazzad Hassan, Fiona Williams, Niranjan Awasthi, Margaret A. Schwarz, Roderich E. Schwarz, Urs von Holzen. Synergistic effects of foretinib with lapatinib in MET and HER2 co-activated experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4826.