Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
iThree Institute, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
Int J Mol Sci. 2021 Aug 7;22(16):8506. doi: 10.3390/ijms22168506.
Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes or that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of . In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.
几种聚（二磷酸腺苷核糖）聚合酶（PARP）抑制剂目前已用于治疗 BReast CAncer 基因缺陷或同源重组修复（HRR）功能不足的肿瘤。奥拉帕利、尼拉帕利或鲁卡帕利用于治疗高级别浆液性卵巢癌，包括维持治疗，延长了患有这种恶性肿瘤的女性的无进展生存期和总生存期。虽然不同的 PARP 抑制剂（PARPi）在机制上相似，但在化学结构、毒性谱、PARP 捕获能力和多药理学景观方面存在差异。我们用五种 PARPi（奥拉帕利、尼拉帕利、鲁卡帕利、他拉唑帕利和 veliparib）治疗了已知 状态的卵巢癌细胞系模型，包括配对细胞系 PEO1 和 PEO4，以及 UWB1.289 和 UWB1.289+BRCA1，并观察到 PARPi 在细胞活力和细胞存活方面的差异。对 veliparib 获得性耐药的细胞系模型显示对其他四种测试的 PARPi 具有更高的耐药性，这表明对一种 PARPi 的获得性耐药可能无法被另一种 PARPi 挽救。最后，作为一个原理验证，通过耗尽 使 HRR 功能正常的卵巢癌细胞对 PARPi 敏感。在未来，需要制定指南，以帮助临床医生将特定的 PARPi 与特定的患者和肿瘤相匹配。
