ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27

Yong Wang, Yanan Wang, Lei Bao, Goncalo Vale, Jeffrey G. McDonald, Yisheng Fang, Yan Peng, Ashwani Kumar, Chao Xing, Fara Brasó-Maristany, Aleix Prat, Carlos L. Arteaga, Yingfei Wang and Weibo Luo ()
Additional contact information
Yong Wang: UT Southwestern Medical Center
Yanan Wang: UT Southwestern Medical Center
Lei Bao: UT Southwestern Medical Center
Goncalo Vale: UT Southwestern Medical Center
Jeffrey G. McDonald: UT Southwestern Medical Center
Yisheng Fang: UT Southwestern Medical Center
Yan Peng: UT Southwestern Medical Center
Ashwani Kumar: UT Southwestern Medical Center
Chao Xing: UT Southwestern Medical Center
Fara Brasó-Maristany: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Aleix Prat: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Carlos L. Arteaga: UT Southwestern Medical Center
Yingfei Wang: UT Southwestern Medical Center
Weibo Luo: UT Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59184-5

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