Olaparib combined with CDK12-IN-3 to promote genomic instability and cell death in ovarian cancer.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.94568
Jianqiang Liang, Xuan Zhou, Lin Yuan, Tian Chen, Yicong Wan, Yi Jiang, Huangyang Meng, Mengting Xu, Lin Zhang, Wenjun Cheng
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引用次数: 0

Abstract

Large-scale phase III clinical trials of Olaparib have revealed benefits for ovarian cancer patients with BRCA gene mutations or homologous recombination deficiency (HRD). However, fewer than 50% of ovarian cancer patients have both BRCA mutations and HRD. Therefore, improving the effect of Olaparib in HR-proficient patients is of great clinical value. Here, a combination strategy comprising Olaparib and CDK12-IN-3 effectively inhibited the growth of HR-proficient ovarian cancer in cell line, patient-derived organoid (PDO), and mouse xenograft models. Furthermore, the combination strategy induced severe DNA double-strand break (DSB) formation, increased NHEJ activity in the G2 phase, and reduced HR activity in cancer cells. Mechanistically, the combination treatment impaired Ku80 poly(ADP-ribosyl)ation (PARylation) and phosphorylation, resulting in PARP1-Ku80 complex dissociation. After dissociation, Ku80 occupancy at DSBs and the resulting Ku80-primed NHEJ activity were increased. Owing to Ku80-mediated DNA end protection, MRE11 and Rad51 foci formation was inhibited after the combination treatment, suggesting that this treatment suppressed HR activity. Intriguingly, the combination strategy expedited cGAS nuclear relocalization, further suppressing HR and, conversely, increasing genomic instability. Moreover, the inhibitory effect on cell survival persisted after drug withdrawal. These findings provide a rationale for the clinical application of CDK12-IN-3 in combination with Olaparib.

奥拉帕利(Olaparib)与 CDK12-IN-3 结合可促进卵巢癌的基因组不稳定性和细胞死亡。
奥拉帕利(Olaparib)的大规模III期临床试验显示,BRCA基因突变或同源重组缺陷(HRD)的卵巢癌患者可从中获益。然而,只有不到50%的卵巢癌患者同时存在BRCA基因突变和同源重组缺陷。因此,提高奥拉帕利在HR缺陷患者中的疗效具有重要的临床价值。在此研究中,奥拉帕利和CDK12-IN-3的组合策略有效抑制了HR缺陷卵巢癌在细胞系、患者衍生类器官(PDO)和小鼠异种移植模型中的生长。此外,联合策略还诱导了严重的DNA双链断裂(DSB)形成,提高了G2期的NHEJ活性,降低了癌细胞的HR活性。从机理上讲,联合疗法损害了Ku80的聚(ADP-核糖基)化(PAR)和磷酸化,导致PARP1-Ku80复合物解离。解离后,Ku80在DSB上的占有率和由此产生的Ku80-primed NHEJ活性都增加了。由于 Ku80 介导的 DNA 末端保护,MRE11 和 Rad51 病灶的形成在联合处理后受到抑制,这表明该处理抑制了 HR 活性。耐人寻味的是,联合策略加快了 cGAS 核再定位,进一步抑制了 HR,相反,增加了基因组的不稳定性。此外,对细胞存活的抑制作用在停药后依然存在。这些发现为CDK12-IN-3与奥拉帕利联合应用于临床提供了理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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