Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50% of HGSOC are characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARP inhibitors have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients.

The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response.

卵巢癌是代表最常见组织学亚型的高级别浆液性癌 (HGSOC) 女性癌症相关死亡的第五大原因。大约 50% 的 HGSOC 的特征是同源重组 (HR) 缺陷，这是修复 DNA 双链断裂的主要细胞途径之一，并且已充分描述的机制之一是BRCA1或BRCA2基因的功能丧失。多聚 ADP-核糖聚合酶 (PARP) 的抑制在 HR 缺陷时是合成致死的，使用 PARP 抑制剂 (PARPi) 显着改善了 HGSOC 患者的预后，对BRCA1/2患者的益处更大肿瘤不足。然而，对 PARPi 的内在或获得性耐药不可避免地发生在大多数 HGSOC 患者中。已经描述了对 PARP 抑制剂耐药的不同异质机制，包括由于多药外排泵的上调导致细胞内药物水平降低、PARP1 蛋白表达缺失/失活突变、HR 恢复和复制叉的保护。破译对 PARPi 耐药的分子机制对于开发新的治疗策略和/或新的药物以克服这种化学耐药性并优化个体 HGSOC 患者的治疗方案至关重要。

目前的综述总结了对 PARPi 耐药的机制、关于新的联合治疗策略（与化疗、抗血管生成剂和免疫检查点抑制剂）以及针对 DNA 损伤反应的正在研究中的药物的可用临床前和临床数据。