GPX4
聚ADP核糖聚合酶
癌症研究
PARP1
生物
癌细胞
合成致死
癌症
遗传学
DNA修复
基因
谷胱甘肽
谷胱甘肽过氧化物酶
酶
生物化学
聚合酶
作者
Guang Lei,Chao Mao,Amber Horbath,Yizhong Yan,Shirong Cai,Jun Yao,Yan Jiang,Mingchuang Sun,Xiaoguang Liu,Jinrong Cheng,Zhihao Xu,Hyemin Lee,Qidong Li,Zhengdao Lu,Li Jian Zhuang,Mei-Kuang Chen,Amulya Alapati,Timothy A. Yap,Mien‐Chie Hung,M. James You,Helen Piwnica‐Worms,Boyi Gan
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2024-03-28
标识
DOI:10.1158/2159-8290.cd-23-1220
摘要
Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.
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