Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Mol Cancer Ther. 2013 Jun;12(6):1002-15. doi: 10.1158/1535-7163.MCT-12-0813. Epub 2013 May 31.
Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and γH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and γH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer.
在这里，我们研究了 PARP 抑制剂鲁卡帕尼（rucaparib，以前称为 AG014699 和 PF-01367338）在治疗散发性卵巢癌方面的潜在作用。我们研究了鲁卡帕尼在 39 个卵巢癌细胞系中的生长抑制作用，这些细胞系的特征是 BRCA1/2 的突变和甲基化状态、基线基因表达特征、选定基因的拷贝数变异、PTEN 状态以及对铂类化疗的敏感性。为了研究与化疗的相互作用，我们使用了多种药物效应分析，并评估了细胞凋亡、DNA 片段化和 γH2AX 形成。在 39 个细胞系中的 26 个（67%）中观察到鲁卡帕尼的浓度依赖性抗增殖作用，而且不限于具有 BRCA1/2 突变的细胞系。其他同源修复相关基因（如 BCCIP、BRCC3、ATM、RAD51L1）的低表达、AURKA 或 EMSY 的扩增以及对铂类化疗的反应与对鲁卡帕尼的敏感性相关。鲁卡帕尼与拓扑替康的药物相互作用为协同作用，与卡铂、多柔比星或紫杉醇的药物相互作用为协同或相加作用，与吉西他滨的药物相互作用为相加作用。当鲁卡帕尼与拓扑替康联合使用时，协同作用最为明显，导致细胞凋亡、DNA 片段化和 γH2AX 形成增强。重要的是，鲁卡帕尼增强化疗作用独立于其作为单一药物的活性。PARP 抑制可能是治疗同源重组途径缺陷的更广泛卵巢癌的一种有用的治疗策略，而不仅仅是 BRCA1/2 突变。这些结果支持进一步评估鲁卡帕尼作为单一药物或作为化疗辅助药物治疗散发性卵巢癌的临床应用。
