ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
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.
Authors
- Jeffrey G. McDonald (ORCID: https://orcid.org/0000-0003-1570-4142)
- Weibo Luo (ORCID: https://orcid.org/0000-0002-1992-0320)
- Fara Brasó‐Maristany (ORCID: https://orcid.org/0000-0001-5440-9643)
- Yingfei Wang (ORCID: https://orcid.org/0000-0002-8723-252X)
- Carlos L. Arteaga (ORCID: https://orcid.org/0000-0003-0870-9586)
- Ashwani Kumar (ORCID: https://orcid.org/0000-0003-4099-935X)
- Yan Peng (ORCID: https://orcid.org/0000-0001-6579-3409)
- Gonçalo Vale (ORCID: https://orcid.org/0000-0003-1104-0289)
- Aleix Prat (ORCID: https://orcid.org/0000-0003-2377-540X)
- Yong Wang (ORCID: https://orcid.org/0009-0001-0953-5824)
- Lei Bao (ORCID: https://orcid.org/0000-0002-1347-8543)
- Chao Xing (ORCID: https://orcid.org/0000-0002-1838-0502)
- Yanan Wang (ORCID: https://orcid.org/0000-0002-7433-3567)
- Yisheng Fang
Institutions
- Southwestern Medical Center (US)
- Hospital Quirónsalud Barcelona (ES)
- Hospital Clínic de Barcelona (ES)
- Oryzon Genomics (Spain) (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Southwestern Medical Center (US)
- Universitat de Barcelona (ES)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s41467-025-59184-5
- Citations
- 8
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 10.88
Funders
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- National Cancer Institute