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N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer

Author

Listed:
  • Yutian Zou

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Shaoquan Zheng

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Xinhua Xie

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Feng Ye

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Xiaoqian Hu

    (School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong)

  • Zhi Tian

    (College of Pharmacy, University of South Florida)

  • Shu-Mei Yan

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Lu Yang

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Yanan Kong

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Yuhui Tang

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Wenwen Tian

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Jindong Xie

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Xinpei Deng

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Yan Zeng

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Zhe-Sheng Chen

    (College of Pharmacy and Health Sciences, St. John’s University)

  • Hailin Tang

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

  • Xiaoming Xie

    (Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine)

Abstract

Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe2+ efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer.

Suggested Citation

  • Yutian Zou & Shaoquan Zheng & Xinhua Xie & Feng Ye & Xiaoqian Hu & Zhi Tian & Shu-Mei Yan & Lu Yang & Yanan Kong & Yuhui Tang & Wenwen Tian & Jindong Xie & Xinpei Deng & Yan Zeng & Zhe-Sheng Chen & Ha, 2022. "N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30217-7
    DOI: 10.1038/s41467-022-30217-7
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    References listed on IDEAS

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