ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3

// Eva A. Ebbing 1, 5 , Jan Paul Medema 1, 6 , Helene Damhofer 1 , Sybren L. Meijer 2 , Kausilia K. Krishnadath 1, 3 , Mark I. van Berge Henegouwen 4 , Maarten F. Bijlsma 1, * , Hanneke W. M. van Laarhoven 5, * 1 Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 2 Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 3 Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 4 Department of Surgery, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 5 Department of Medical Oncology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands 6 Cancer Genomics Center, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands * These authors have contributed equally to this work Correspondence to: Eva A. Ebbing, e-mail: e.a.ebbing@amc.uva.nl Keywords: ADAM10, HER3, trastuzumab, NRG-1β, esophageal cancer Abbreviations: ADAM, a disintegrin and metalloproteinase domain-containing protein; EAC, esophageal adenocarcinoma; HER, human epidermal growth factor receptor; RTK, receptor tyrosine kinase Received: September 30, 2015 Accepted: January 23, 2016 Published: February 05, 2016 ABSTRACT 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 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 the cellular mechanisms of resistance to targeted therapeutic agents exists in esophageal adenocarcinoma. Using primary established HER2-overexpressing cultures and patient-derived xenograft models, we now reveal a novel resistance mechanism to trastuzumab in esophageal cancer: In response to trastuzumab, both HER3 and the metalloprotease ADAM10 are simultaneously upregulated. The proteolytic activity of the latter then releases the HER3 ligand heregulin from the cell surface to activate HER3 and confer resistance to trastuzumab by inducing compensatory growth factor receptor signaling. Blocking either HER3 or ADAM10 effectively reverts the acquired resistance to trastuzumab. Our data thus provide strategies to inhibit this signaling and circumvent resistance to trastuzumab.