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

Author

Listed:
  • Yong Wang

    (UT Southwestern Medical Center)

  • Yanan Wang

    (UT Southwestern Medical Center)

  • Lei Bao

    (UT Southwestern Medical Center)

  • Goncalo Vale

    (UT Southwestern Medical Center
    UT Southwestern Medical Center)

  • Jeffrey G. McDonald

    (UT Southwestern Medical Center
    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
    UT Southwestern Medical Center)

  • Fara Brasó-Maristany

    (August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
    Hospital Clínic of Barcelona
    S.L.)

  • Aleix Prat

    (August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
    Hospital Clínic of Barcelona
    S.L.
    University of Barcelona)

  • Carlos L. Arteaga

    (UT Southwestern Medical Center)

  • Yingfei Wang

    (UT Southwestern Medical Center
    UT Southwestern Medical Center
    UT Southwestern Medical Center
    UT Southwestern Medical Center)

  • Weibo Luo

    (UT Southwestern Medical Center
    UT Southwestern Medical Center
    UT Southwestern Medical Center)

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.

Suggested Citation

  • 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 & Wei, 2025. "ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59184-5
    DOI: 10.1038/s41467-025-59184-5
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    References listed on IDEAS

    as
    1. Finnur Freyr Eiriksson & Martha Kampp Nøhr & Margarida Costa & Sigridur Klara Bödvarsdottir & Helga Margret Ögmundsdottir & Margret Thorsteinsdottir, 2020. "Lipidomic study of cell lines reveals differences between breast cancer subtypes," PLOS ONE, Public Library of Science, vol. 15(4), pages 1-22, April.
    2. Johannes Zuber & Junwei Shi & Eric Wang & Amy R. Rappaport & Harald Herrmann & Edward A. Sison & Daniel Magoon & Jun Qi & Katharina Blatt & Mark Wunderlich & Meredith J. Taylor & Christopher Johns & A, 2011. "RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia," Nature, Nature, vol. 478(7370), pages 524-528, October.
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