Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway
Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway
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紫杉醇通过 CDK1/BRCA1 途径使同源重组能力强的卵巢癌细胞对 PARP 抑制剂敏感
DOI：
10.1016/j.ygyno.2022.11.006
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Okamoto A.
中科院分区：
文献类型：
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作者：
Yanaihara N;Yoshino Y;Noguchi D;Tabata J;Takenaka M;Iida Y;Saito M;Yanagida S;Iwamoto M;Kiyokawa T;Chiba N;Okamoto A.
目的：虽然聚（adp -核糖）聚合酶抑制剂（PARPi）对同源重组（HR）精通（HRP）表型的上皮性卵巢癌（EOC）的病程有影响，但尚未建立有效的治疗策略。在此，我们旨在阐明紫杉醇（PTX）对DNA损伤反应的细胞作用以及PTX与PARPi在HRP卵巢癌中的治疗应用。方法建立两种不同给药方案的HRP卵巢癌OVISE细胞模型。在添加或不添加PARPi的模型中分析生长抑制和HR活性。通过抑制CDK1，在OVISE细胞中检测BRCA1磷酸化状态，PTX治疗降低了CDK1。在接受ptx为基础的新辅助化疗的EOC患者中评估CDK1的表达。结果sptx抑制CDK1表达，导致OVISE细胞BRCA1磷酸化受损。PTX降低CDK1活性可降低HR对DNA损伤的反应活性，从而增加对PARPi的敏感性。免疫组织化学显示，与化疗前相比，ptx化疗后收集的样本中CDK1表达减弱。与常规PTX方案相比，剂量密集PTX方案CDK1表达的下降幅度更大。结论在HRP卵巢癌细胞中，sptx可与PARPi协同作用，提示PTX联合PARPi可能是一种新的治疗策略，将PARPi的应用扩展到EOC。我们的研究结果为未来评估PTX联合PARPi治疗HRP卵巢癌的疗效的转化临床试验提供了线索。
ObjectiveAn effective treatment strategy for epithelial ovarian cancer (EOC) with homologous recombination (HR)-proficient (HRP) phenotype has not been established, although poly (ADP-ribose) polymerase inhibitors (PARPi) impact the disease course with HR-deficient (HRD) phenotype. Here, we aimed to clarify the cellular effects of paclitaxel (PTX) on the DNA damage response and the therapeutic application of PTX with PARPi in HRP ovarian cancer.MethodsTwo models with different PTX dosing schedules were established in HRP ovarian cancer OVISE cells. Growth inhibition and HR activity were analyzed in these models with or without PARPi. BRCA1 phosphorylation status was examined in OVISE cells by inhibiting CDK1, which was reduced by PTX treatment. CDK1 expression was evaluated in EOC patients treated with PTX-based neoadjuvant chemotherapy.ResultsPTX suppressed CDK1 expression resulting in impaired BRCA1 phosphorylation in OVISE cells. The reduced CDK1 activity by PTX could decrease HR activity in response to DNA damage and therefore increase the sensitivity to PARPi. Immunohistochemistry showed that CDK1 expression was attenuated in samples collected after PTX-based chemotherapy compared to those collected before chemotherapy. The decrease in CDK1 expression was greater with dose-dense PTX schedule than with the conventional PTX schedule.ConculsionsPTX could act synergistically with PARPi in HRP ovarian cancer cells, suggesting that the combination of PTX with PARPi may be a novel treatment strategy extending the utility of PARPi to EOC. Our findings provide cules for future translational clinical trials evaluating the efficacy of PTX in combination with PARPi in HRP ovarian cancer.