2. Academic Validation
  3. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer

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

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. chenz@stjohns.edu.
  • 5 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. tanghl@sysucc.org.cn.
  • 6 Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. xiexm@sysucc.org.cn.
  • # 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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