Ebbing Eva A, Medema Jan Paul, Damhofer Helene, Meijer Sybren L, Krishnadath Kausilia K, van Berge Henegouwen Mark I, Bijlsma Maarten F, van Laarhoven Hanneke W M
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.
Oncotarget. 2016 Mar 1;7(9):10243-54. doi: 10.18632/oncotarget.7200.
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.
HER家族的受体酪氨酸激酶参与多种上皮肿瘤的发生和发展，因此已成为新型抗癌疗法广泛使用的靶点。曲妥珠单抗是一种抗HER2抗体，已显示出对包括胃癌在内的HER2过表达肿瘤具有强大的生长抑制作用，然而，对这种疗法产生耐药性是不可避免的。不幸的是，在食管腺癌中，关于对靶向治疗药物耐药的细胞机制的数据很少。利用原发性建立的HER2过表达培养物和患者来源的异种移植模型，我们现在揭示了食管癌中对曲妥珠单抗的一种新的耐药机制：在曲妥珠单抗作用下，HER3和金属蛋白酶ADAM10同时上调。后者的蛋白水解活性随后从细胞表面释放HER3配体神经调节蛋白，以激活HER3并通过诱导代偿性生长因子受体信号传导赋予对曲妥珠单抗的耐药性。阻断HER3或ADAM10可有效逆转对曲妥珠单抗获得性耐药。因此，我们的数据提供了抑制这种信号传导并规避对曲妥珠单抗耐药的策略。
