Strategies in Overcoming Homologous Recombination Proficiency and PARP Inhibitor Resistance.
Strategies in Overcoming Homologous Recombination Proficiency and PARP Inhibitor Resistance.
复制标题
克服同源重组能力和PARP抑制剂耐药性的策略。
DOI：
10.1158/1535-7163.mct-20-0992
复制
发表时间：
2021-09
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
卵巢癌是美国第二大常见妇科恶性肿瘤，也是妇科癌症相关死亡的最常见原因。尽管前期以铂和紫杉烷为基础的化疗有效率很高，但大多数卵巢癌最终仍会复发。近年来，一线治疗后的维持治疗已成为延长这些患者无铂期的有效工具。尤其是PARP抑制剂（PARPis）的维持治疗，已成为前期治疗和铂敏感疾病患者标准治疗的一部分。同源重组缺陷（HRD）肿瘤具有无功能的同源重组修复（HRR）途径，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，HRR通路功能正常的患者，即HRR精通的肿瘤，仍然可以从PARPi中获益，但效果不如HRD肿瘤显著。由于HR熟练，parpi在一些患者中无效，这要么是肿瘤固有的，要么是潜在的获得性，作为治疗耐药性的一种方法。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，无论是获得性的还是肿瘤固有的。
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.