Abstract 400: ERBB2 Inhibition Leads to Cardiac Dysfunction

Abstract

Growth factor ERBB2 inhibition is a reliable treatment for patients diagnosed with breast cancer but is known to cause cardiotoxicity, resulting in dysfunction and dilation. In our studies, we have taken a unique approach with the premise that ERBB2 inhibitors like trastuzumab or pertuzumab binding to ERBB2 may lead to a conformation that could engage/activate non-canonical signals while inhibiting classical pathways. Such non-canonical activation of signals by inhibitor may be beneficial for treating cancer, while the same pathways could be detrimental in the cardiomyocytes. Our data is further suppored by the microRNA-7 Transgenic mice developed in our lab, which downregulates ERBB2 leading to cardiac dysfunction as seen by echocardiography. These studies will lay the foundation for developing strategies that could specifically block the deleterious effect of ERBB2 inhibitors on the heart. Moreover, administration of AG825 in mice for two weeks results in significant cardiac dysfunction and dilation compared to AG1875 or vehicle controls, conferring the idea that inhibition of ERBB2 and not EGFR that mediates deleterious remodeling. Furthermore, mitochondria morphology was also affected upon ERBB2 inhibition as seen in our microRNA-7 transgenic mice hearts as well as AG825 (ERBB2 inhibtor) treated mice in the electrom micrographs. We will also discuss the proteomics analysis in the ERBB2 inhibitor treated hearts, microRNA-7 Transgenic mice hearts, ERBB2 transgenic mice hearts as compared to the C57/BL6 wildtype hearts. Our studies therefore aims to target these non-canonical signals in the heart with an idea to insulate the heart from the deleterious effects of chemotherapy.