Abstract 4935: T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways

Abstract

Abstract Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate developed to treat trastuzumab-resistant cancer. Despite initial favorable outcomes, most patients eventually cease to respond by developing acquired resistance to T-DM1. Currently, there is no targeted therapy to treat T-DM1-resistant cancer. To explore novel therapeutic targets to overcome T-DM1 resistance, we generated T-DM1-resistant cells using trastuzumab-resistant JIMT1 cells. We found that the loss of human epidermal growth factor receptor 2 (HER2) confers T-DM1 resistance, which in turn activates a compensatory mechanism that increases epidermal growth factor receptor (EGFR) expression. Upregulation of EGFR increases the protein levels of α5β1 integrin, resulting in enhanced motility and invasion of T-DM1-resistant cells. However, silencing β1 integrin expression by siRNA or β1 integrin blockage induced by an inhibitory antibody, MAB 13, significantly increases invasion of T-DM1-resistant cells. The discovery of functional cooperation between EGFR and integrin in regulating cell growth and invasion provides an opportunity to develop novel therapeutic strategy by dual-targeting EGFR and specific integrin to overcome T-DM1 resistance. We now try to identify downstream molecules involved in the increased invasion using next generation sequencing (NGS) technology in β1 integrin-deficient T-DM1 resistant cells. Citation Format: Yukinori Endo, Zachary Olson, Wen Jin Wu. T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4935.