Abstract
Abstract Esophageal adenocarcinoma is an aggressive malignancy and its incidence is rapidly increasing. Despite multimodality treatment, patients face a poor 5-year survival of 15-25%, underscoring the urgency to improve treatment strategies. Receptor tyrosine kinases of the HER-family are involved in the development and progression of multiple epithelial tumors, and have consequently become widely used targets for the development of new anti-cancer therapies. Trastuzumab, an antibody against HER2, has shown potent growth inhibitory effects on HER2 overexpressing tumors, including gastro-esophageal cancer, however, resistance to this therapy is inevitable. Unfortunately, a paucity of data on cellular mechanisms of resistance to targeted therapeutic agents exist in esophageal adenocarcinoma. In order to study the effect of HER2 inhibition in vitro and in vivo, we established unique primary cultures of esophageal adenocarcinoma and patient-derived xenograft models. Using these novel tools, we demonstrate a conserved, hard-wired mechanism in which HER3 is upregulated upon trastuzumab-induced resistance in esophageal adenocarcinoma. Furthermore, blocking upregulated HER3 effectively resulted in a strong decrease in cell viability and induced cell death. Taken together, our data provide preclinical insight that strategies targeting HER3 in combination with trastuzumab could possibly prevent acquired resistance. Citation Format: Eva A. Ebbing, Jan Paul Medema, Sybren L. Meijer, Kausilia K. Krishnadath, Mark I. van Berge Henegouwen, Maarten F. Bijlsma, Hanneke W. M. van Laarhoven. HER3 mediates acquired resistance to HER2-targeted therapy in esophageal adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 350. doi:10.1158/1538-7445.AM2015-350
Published Version
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