Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
Department of Cancer Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan.
Gynecol Oncol. 2023 Jan;168:83-91. doi: 10.1016/j.ygyno.2022.11.006. Epub 2022 Nov 17.
An 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.
Two 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.
PTX 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.
PTX 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.
尽管聚（ADP-核糖）聚合酶抑制剂（PARPi）对同源重组缺陷（HRD）表型的疾病进程有影响，但对于同源重组（HR）功能正常（HRP）表型的上皮性卵巢癌（EOC）尚未确立有效的治疗策略。本研究旨在阐明紫杉醇（PTX）对 DNA 损伤反应的细胞效应以及 PTX 联合 PARPi 在 HRP 卵巢癌中的治疗应用。
在 HRP 卵巢癌 OVISE 细胞中建立了两种不同 PTX 给药方案的模型。在这些模型中分析了有无 PARPi 存在时的生长抑制和 HR 活性。通过抑制 CDK1 来检测 OVISE 细胞中 BRCA1 的磷酸化状态，而 CDK1 的表达则因 PTX 处理而减少。评估了接受以 PTX 为基础的新辅助化疗的 EOC 患者的 CDK1 表达。
PTX 抑制 CDK1 的表达，导致 OVISE 细胞中 BRCA1 的磷酸化减少。PTX 降低 CDK1 活性可降低 DNA 损伤后的 HR 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，接受以 PTX 为基础的化疗后样本中 CDK1 的表达减弱。与常规 PTX 方案相比，密集型 PTX 方案中 CDK1 表达的下降更为明显。
PTX 可与 HRP 卵巢癌细胞中的 PARPi 协同作用，表明 PTX 与 PARPi 的联合可能是一种将 PARPi 扩展用于 EOC 的新的治疗策略。我们的研究结果为未来评估 PTX 联合 PARPi 在 HRP 卵巢癌中的疗效的转化临床研究提供了依据。
