Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2024 Aug 2;14(8):1476-1495. doi: 10.1158/2159-8290.CD-23-1220.
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 patients with BRCA1-mutant breast cancer 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. Significance: BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers. See related commentary by Alborzinia and Friedmann Angeli, p. 1372.
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）缺陷型癌症中的治疗效果。在这里，我们揭示 BRCA1 在调节铁死亡中具有双重作用。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 缺陷会促进细胞对依立替康诱导的铁死亡的耐药性，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 联合治疗时，会在 BRCA1 缺陷型癌细胞中释放强大的铁死亡。最后，我们发现，对 PARPi 耐药的 BRCA1 突变型乳腺癌的异种移植瘤表现出 GPX4 表达降低和对 PARP 和 GPX4 联合抑制的高敏感性。我们的研究结果表明，BRCA1 缺陷会导致对 PARP 和 GPX4 联合抑制的铁死亡易感性，并为克服 BRCA1 缺陷型癌症中 PARPi 耐药提供了一种治疗策略。意义：BRCA1 缺陷通过阻断 VDAC3 促进对依立替康诱导的铁死亡的耐药性，但通过抑制 GPX4 使癌细胞对 GPX4i 诱导的铁死亡敏感。NCOA4 的诱导和缺陷的 GPX4 进一步协同 GPX4i 与 PARPi 诱导 BRCA1 缺陷型癌症中的铁死亡，并靶向 GPX4 减轻这些癌症中的 PARPi 耐药性。见相关评论由 Alborzinia 和 Friedmann Angeli，第 1372 页。
