Abstract 3075: Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity

Abstract

Abstract Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. Using human primary cardiomyocytes as a model, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity. This downregulation of TOP2B in turn induces DNA damage activity and DNA double strand breaks. However, unlike doxorubicin, trastuzumab alone does not induce apoptosis. Further investigation discovers that concurrent or sequential treatment of doxorubicin and trastuzumab significantly reduces protein levels of TOP2B, enhances apoptosis induced by doxorubicin, and inhibits cell growth. Furthermore, treatment of cardiomyocytes with doxorubicin and trastuzumab in either concurrent or sequential setting also enhances production of reactive oxidative and nitrative species as compared to either trastuzumab or doxorubicin treatment in cardiomyocytes. Our data reveal that doxorubicin treatment increases the cellular level of ErbB2/HER2 protein and enhances downstream signaling activity of this pathway. Consequently, this may render cardiomyocytes more sensitive to trastuzumab treatment after doxorubicin exposure. This study provides molecular basis for significantly increased cardiotoxicity in cancer patients treated with anthracyclines and trastuzumab-based combination regimens. Citation Format: Jiangsong Jiang, Nishant Mohan, Yukinori Endo, Yi Shen, Wen Jin Wu. Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3075.