ZNF689的缺失削弱了同源重组对PARP和PD-L1联合抑制的敏感性
ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition.
摘要(中文译文)
三阴性乳腺癌（TNBC）是乳腺癌中侵袭性最强的亚型，由于缺乏有效的靶向治疗手段，其预后较差。尽管聚（ADP-核糖）聚合酶（PARP）抑制剂对BRCA1/2突变的TNBC患者有益，但其在BRCA野生型肿瘤中的疗效仍然有限。在本研究中，我们揭示了锌指蛋白689（ZNF689）在调控TNBC同源重组（HR）修复中的关键作用。我们的研究发现，在DNA损伤应答中，ZNF689被ATM磷酸化，并通过E3连接酶SKP2促进NBS1泛素化，从而导致MRN复合物的稳定及随后的ATM激活，进而促进HR修复。ZNF689缺失显著增强TNBC对PARP抑制剂的敏感性，尤其是在与紫杉醇联合使用时。此外，PARP抑制通过激活STING通路上调ZNF689缺陷型TNBC细胞中PD-L1的表达。值得注意的是，ZNF689缺失增强了PARP抑制联合抗PD-L1免疫治疗的疗效。综上所述，这些发现表明ZNF689是HR修复的关键调控因子，并为在ZNF689低表达TNBC患者中联合应用PARP抑制与PD-L1阻断提供了概念验证。
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by a poor prognosis due to the lack of effective targeted therapies. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit BRCA1/2-mutated TNBC, their efficacy in BRCA wild-type tumors remains limited. In this study, we uncover a critical role of zinc-finger protein 689 (ZNF689) in regulating homologous recombination (HR) repair in TNBC. Our findings reveal that in response to DNA damage, ZNF689 is phosphorylated by ATM and promotes NBS1 ubiquitination via E3 ligase SKP2, leading to the stabilization of the MRN complex and subsequent ATM activation, thereby facilitating HR repair. ZNF689 loss markedly enhances sensitivity to PARP inhibitors in TNBC, particularly when combined with paclitaxel. Furthermore, PARP inhibition upregulates PD-L1 expression in ZNF689-deficient TNBC cells through activation of the STING pathway. Notably, ZNF689 loss enhances the therapeutic efficacy of PARP inhibition plus anti-PD-L1 immunotherapy. Together, these findings suggest ZNF689 as a crucial regulator of HR repair and provide proof-of-concept for combining PARP inhibition and PD-L1 blockade in patients with ZNF689-low TNBC.
如何引用
AMA
Li-Ping Ge, Yu-Ling Xiao, Song-Yang Wu, Fang-Lin Zhang, Eo-Ryeong Lee, Gen-Hong Di, et al. ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition.. Nature communications. 2026; doi:10.1038/s41467-026-75031-7.
APA
Li-Ping Ge, Yu-Ling Xiao, Song-Yang Wu, Fang-Lin Zhang, Eo-Ryeong Lee, Gen-Hong Di, et al (2026). ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition.. Nature communications. https://doi.org/10.1038/s41467-026-75031-7
GB/T 7714
Li-Ping Ge, Yu-Ling Xiao, Song-Yang Wu, Fang-Lin Zhang, Eo-Ryeong Lee, Gen-Hong Di, et al. ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75031-7.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出