Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma

Md Sazzad Hassan,Urs Von Holzen,Margaret A Schwarz,Niranjan Awasthi,Fiona Williams,Jun Li,Roderich E Schwarz

doi:10.1038/s41598-019-54129-7

Abstract

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.

Highlights

Recent studies have demonstrated that human epidermal growth factor receptor 2 (HER2) and MET receptor tyrosine kinases are co-overexpressed in a subset esophageal adenocarcinoma (EAC)
We found that the OE33 EAC cell line showed very strong phosphorylation of both MET and HER2, whereas OE19 cells showed phosphorylation of mainly HER2, and ESO51 showed phosphorylation of largely MET
OE33 EAC cells with MET and HER2 co-activation were resistant to single-agent MET-targeting foretinib (0.1 μM), and HER2-targeting lapatinib (1 μM) induced inhibition of cell growth, but showed significantly enhanced cell growth inhibition when foretinib and lapatinib were co-administered (Fig. 2a)

Summary

Introduction

Recent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset esophageal adenocarcinoma (EAC). We 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. 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. We hypothesized that MET activation may lead to lapatinib resistance in HER2-driven esophageal adenocarcinoma, and tested the feasibility of MET targeting by small-molecule inhibitor Foretinib in EAC cells.

Methods

Results

Conclusion