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

  • Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7.
Yutian Zou   #  1 ,  Shaoquan Zheng   #  1 ,  Xinhua Xie   #  1 ,  Feng Ye  1 ,  Xiaoqian Hu  2 ,  Zhi Tian  3 ,  Shu-Mei Yan  1 ,  Lu Yang  1 ,  Yanan Kong  1 ,  Yuhui Tang  1 ,  Wenwen Tian  1 ,  Jindong Xie  1 ,  Xinpei Deng  1 ,  Yan Zeng  1 ,  Zhe-Sheng Chen  4 ,  Hailin Tang  5 ,  Xiaoming Xie  6
Affiliations
  • 1. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 2. School of Biomedical Sciences, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3. College of Pharmacy, University of South Florida, Tampa, FL, USA.
  • 4. College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA. [email protected].
  • 5. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. [email protected].
  • 6. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 35562334 DOI: 10.1038/s41467-022-30217-7
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.

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