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

• Published in: Nature communications 2022-05, Vol.13 (1), p.2672-2672, Article 2672
• Main Authors: Zou, Yutian, Zheng, Shaoquan, Xie, Xinhua, Ye, Feng, Hu, Xiaoqian, Tian, Zhi, Yan, Shu-Mei, Yang, Lu, Kong, Yanan, Tang, Yuhui, Tian, Wenwen, Xie, Jindong, Deng, Xinpei, Zeng, Yan, Chen, Zhe-Sheng, Tang, Hailin, Xie, Xiaoming
• Format: Article
• Language: English
• Subjects: 13/1; 38/77; 631/67/1059; 631/67/1059/2326; 631/80/82; 64/60; 692/699/67; 96/109; Adenosine - analogs & derivatives; Adenosine - pharmacology; Apoptosis; beta Catenin; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Death; Cell Line, Tumor; CRISPR; Drug Resistance, Neoplasm - genetics; Efflux; ErbB-2 protein; Female; Ferroptosis; Fibroblast growth factor receptor 4; Genomes; Glutathione; Glycogen Synthase Kinase 3 beta; Humanities and Social Sciences; Humans; Iron; multidisciplinary; N6-methyladenosine; Organoids; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Science; Science (multidisciplinary); Sensitivity enhancement; Synergistic effect; Xenografts; Xenotransplantation; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30217-7

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 Fe 2+ 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. Anti-HER2 resistance causes treatment failure in HER2-positive breast cancers. Here the authors identify FGFR4 as one of the vulnerabilities of anti-HER2 resistant breast cancer and show that FGRR4 inhibition enhances sensitivity to anti-HER2 treatment in these resistant cells by triggering ferroptosis.