ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
Yong Wang, Yanan Wang, Lei Bao, Gonçalo Vale, Jeffrey G. McDonald, Yisheng Fang, Yan Peng, Ashwani Kumar, Chao Xing, Fara Brasó‐Maristany, Aleix Prat, Carlos L. Arteaga, Yingfei Wang, Weibo Luo
Abstract
Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer. While HER2-targeted therapies such as trastuzumab can be effective in patients with breast cancer, resistance often develops. Here, the authors demonstrate that the histone reader ZYMND8 promotes glycerophospholipid metabolic reprogramming via c-Myc and cPLA2α to increase secretion of IL-27, mediating resistance to HER2-targeted antibodies in preclinical models of breast cancer.