title: ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3.
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.
authors: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.|Department of Medical Oncology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Eva A
authors: EA
authors: Ebbing
authors: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.|Cancer Genomics Center, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Jan Paul
authors: JP
authors: Medema
authors: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Helene
authors: H
authors: Damhofer
authors: Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Sybren L
authors: SL
authors: Meijer
authors: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Kausilia K
authors: KK
authors: Krishnadath
authors: Department of Surgery, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Mark I
authors: MI
authors: van Berge Henegouwen
authors: Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Maarten F
authors: MF
authors: Bijlsma
authors: Department of Medical Oncology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors: Hanneke W M
authors: HW
authors: van Laarhoven
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D008565:Membrane Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C491236:ADAM10 protein, human
keywords: ADAM10; HER3; NRG-1β; esophageal cancer; trastuzumab