乳腺癌
癌症研究
癌细胞
体内
癌症
程序性细胞死亡
生物
基因组不稳定性
医学
细胞凋亡
DNA损伤
遗传学
DNA
作者
Yutian Zou,Shaoquan Zheng,Xinhua Xie,Feng Ye,Xiaoqian Hu,Zhi Tian,Shumei Yan,Lu Yang,Yanan Kong,Yuhui Tang,Wenwen Tian,Jun Xie,Xinpei Deng,Yan Zeng,Zhe‐Sheng Chen,Hailin Tang,Xiaoming Xie
标识
DOI:10.1038/s41467-022-30217-7
摘要
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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