SCI

18 July 2024

BRCA1-mediated dual regulation of ferr optosisexposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers

（Cancer discovery；IF：29.7）

  • Lei G, Mao C, Horbath AD, Yan Y, Cai S, Yao J, Jiang Y, Sun M, Liu X, Cheng J, Xu Z, Lee H, Li Q, Lu Z, Zhuang L, Chen MK, Alapati A, Yap TA, Hung MC, You MJ, Piwnica-Worms H, Gan B. BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers. Cancer Discov. 2024 Mar 28. doi: 10.1158/2159-8290.CD-23-1220. Epub ahead of print. PMID: 38552003

  • Corresponding Authors: Guang Lei, Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Unit 1052 Houston, TX 77030. Email: glei@mdanderson.org; and Boyi Gan, bgan@mdanderson.org

Abstract 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.

对聚ADP-核糖聚合酶抑制剂（PARPi）的耐药性限制了PARP抑制在治疗乳腺癌易感基因1（BRCA1）缺陷癌症中的治疗效果。在此，我们揭示了BRCA1在调节铁死亡中的双重作用。BRCA1促进电压依赖性阴离子通道3（VDAC3）和谷胱甘肽过氧化物酶4（GPX4）的转录；因此，BRCA1缺陷促进了细胞对依赖酯的铁死亡的抵抗，但使癌细胞对GPX4抑制剂（GPX4i）诱导的铁死亡敏感。此外，核受体共激活因子4（NCOA4）介导的铁蛋白自噬和缺陷的GPX4诱导在PARPi和GPX4i联合治疗下释放出强烈的铁死亡作用在BRCA1缺陷的癌细胞中。最后，我们揭示，从具有PARPi耐药性的BRCA1突变乳腺癌患者衍生的异种移植肿瘤表现出GPX4表达减少并对PARP和GPX4联合抑制高度敏感。我们的研究结果表明，BRCA1缺陷诱导了对PARP和GPX4联合抑制的铁死亡脆弱性，并提出了一种克服BRCA1缺陷癌症中PARPi耐药性的治疗策略。