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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/227115
ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
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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.
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WANG, Yong, WANG, Yanan, BAO, Lei, VALE, Goncalo, MCDONALD, Jeffrey g., FANG, Yisheng, PENG, Yan, KUMAR, Ashwani, XING, Chao, BRASÓ MARISTANY, Fara, PRAT APARICIO, Aleix, ARTEAGA, Carlos l., WANG, Yingfei, LUO, Weibo. ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27. _Nature Communications_. 2025. Vol. 1, núm. 3908. [consulta: 7 de abril de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/227115]