Ovarian cancer is the second most common gynecologic malignancy in the United States and the most common cause of gynecologic cancer–related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum- and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with PARP inhibitors (PARPis), in particular, has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. Homologous recombination deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPis, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, that is, HR-proficient tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPis are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistance—either acquired or inherent to the tumor.

中文翻译：

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克服同源重组能力和 PARP 抑制剂耐药性的策略

卵巢癌是美国第二常见的妇科恶性肿瘤，也是妇科癌症相关死亡的最常见原因。尽管对铂类和紫杉烷类的前期化疗反应率很高，但大多数卵巢癌最终会复发。近年来，一线治疗后的维持治疗已成为延长这些患者无铂间隔的有效工具。特别是使用 PARP 抑制剂 (PARPis) 进行的维持治疗已成为前期环境和铂类敏感疾病患者护理标准的一部分。同源重组缺陷 (HRD) 肿瘤具有无功能的同源重组修复 (HRR) 途径，并且对 PARPis 反应良好，PARPis 通过同时损害 DNA 修复机制来利用合成致死性。相反，具有功能性 HRR 通路的患者，即 HR 熟练的肿瘤，仍然可以从 PARPi 中获得益处，但疗效不如 HRD 肿瘤中所见的那么显着。由于 HR 熟练程度，PARPis 在某些患者中无效，这要么是肿瘤固有的，要么可能是作为治疗抵抗的方法获得的。本综述旨在概述临床医生和科学家目前采用的克服 PARPi 耐药性的策略——无论是获得性还是肿瘤固有的耐药性。