Co-targeting epigenetic and oncogenic enzymes in HER2+ breast cancer

Abstract

Breast cancer is the most prevalent cancer worldwide with over 2 million women diagnosed every year, and caused 685,000 deaths globally in 2020. 15-25% of breast cancer patients overexpress the receptor tyrosine kinase (RTK) human epidermal growth factor receptor 2 (HER2). While several agents that target HER2 have been FDA-approved, metastatic HER2+ breast cancer remains incurable with a median overall survival of 57 months. This dissertation describes a promising therapeutic strategy for HER2+ breast cancers that co-targets HER2 along with an epigenetic enzyme, EZH2. Specifically, we show that EZH2 inhibitors not only enhance baseline responses to HER2 kinase inhibitors, but also sensitize tumors that have become resistant to these agents, triggering cell death and dramatic tumor regression. We further demonstrate that therapeutic efficacy is mediated by the oncoprotein YAP, which dynamically regulates the pro-apoptotic gene BMF in HER2+ breast cancers. Specifically, EZH2 inhibitors trigger the loss of repressive H3K27 methylation marks at proximal BMF-regulatory sequences, which induces the binding of YAP/TEAD complexes. Importantly, in this setting YAP and TEAD repress BMF transcription and protect cells from death. However, subsequent exposure to HER2 kinase inhibitors trigger the release of YAP/TEAD complexes, inducing BMF transcription and apoptosis. Thus, our studies demonstrate that EZH2 and YAP both normally protect HER2+ breast cancers from cell death by buffering the BMF locus through distinct mechanisms, which can be overcome by combining EZH2 and HER2 kinase inhibitors. In summary, this dissertation describes a promising therapeutic strategy with potential clinical relevance and provides insight into specific vulnerabilities of HER2+ breast cancer, which may ultimately lead to new treatments for this disease.