Synthetic Lethality in Ovarian Cancer.
Synthetic Lethality in Ovarian Cancer.
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DOI：
10.1158/1535-7163.mct-21-0500
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发表时间：
2021-11
影响因子：
5.7
通讯作者：
Elias KM
中科院分区：
文献类型：
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作者：
Chandrasekaran A;Elias KM
卵巢癌包括几种不同的恶性肿瘤，其在临床病理特征和预后方面不同。高级别浆液性癌是最常见的组织学亚型，占大多数卵巢癌相关死亡。高级别浆液性卵巢癌（HGSOC）通过手术和铂类化疗进行治疗，但大多数患者复发并死于化疗耐药疾病。合成致死的遗传概念，其中多个基因中的突变的协同作用导致细胞死亡，提供了一个框架，以设计新的治疗方法，以克服卵巢癌的化疗耐药性。最近在了解卵巢癌的基因组结构和遗传驱动因素方面的进展显示了围绕同源DNA修复设计的合成致死策略的潜力。临床试验已验证PARP抑制剂在BRCA 1或BRCA 2突变患者中的高缓解率。在这里，我们讨论了基于卵巢癌遗传背景靶向BRCA-PARP合成致死性背后的生物学原理，以及如何在临床上评估这种方法。将合成致死性的概念应用于靶向非BRCA突变型癌症是一个持续的挑战，我们讨论了使用合成致死性与PARP抑制剂联合或超越PARP抑制剂靶向卵巢癌的新方法。这篇综述还将描述卵巢癌合成致死性的障碍和为卵巢癌患者开发有效靶向药物的新机会。
Ovarian cancers include several distinct malignancies which differ with respect to clinicopathologic features and prognosis. High-grade serous cancer is the most common histologic subtype and accounts for most ovarian cancer–related deaths. High-grade serous ovarian cancer (HGSOC) is treated with surgery and platinum-based chemotherapy, but most patients relapse and succumb to chemoresistant disease. The genetic concept of synthetic lethality, in which the synergy of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to overcome chemoresistance in ovarian cancer. Recent progress in understanding the genomic architecture and hereditary drivers of ovarian cancer has shown potential for synthetic lethality strategies designed around homologous DNA repair. Clinical trials have validated high response rates for PARP inhibitors in patients with BRCA1 or BRCA2 mutations. Here we discuss the biological rationale behind targeting BRCA–PARP synthetic lethality based on genetic context in ovarian cancer and how this approach is being assessed in the clinic. Applying the concept of synthetic lethality to target non–BRCA-mutant cancers is an ongoing challenge, and we discuss novel approaches to target ovarian cancer using synthetic lethality in combination with and beyond PARP inhibitors. This review will also describe obstacles for synthetic lethality in ovarian cancer and new opportunities to develop potent targeted drugs for patients with ovarian cancer.