Medical Oncology, Vedanta Institute of Medical Sciences, Ahmedabad, Gujarat, India.
Medical Oncology, National Cancer Institute, Nagpur, Maharashtra, India.
Indian J Cancer. 2022 Mar;59(Supplement):S119-S129. doi: 10.4103/ijc.IJC_53_21.
Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.
晚期卵巢癌（OC）的标准治疗包括根治性减瘤细胞切除术，随后进行辅助化疗。OC 的一个重要危险因素是遗传易感性，BRCA1 或 BRCA2 突变占遗传性 OC 的大多数。BRCA 中的突变最终会导致遗传改变的积累，因为细胞无法停止并修复 DNA 损伤或进行细胞凋亡，从而导致肿瘤发生。聚（ADP-核糖）聚合酶（PARP）抑制剂已成为管理 BRCA 相关癌症的一种有前途的方法，特别是高级别 OC 和乳腺癌。它们通过在同源重组缺陷（HR）细胞中使复制叉停滞不前，导致 BRCA 突变细胞的合成致死。目前，四种 PARP 抑制剂（奥拉帕利、尼拉帕利、鲁卡帕利和他拉唑帕利）已获得美国食品和药物管理局（FDA）批准，用于 OC、乳腺癌和胰腺癌适应症，并正在评估其他 BRCA 相关癌症的应用。尽管它们具有临床疗效，但癌细胞通常会通过多种机制对其产生耐药性。了解这些机制对于制定克服耐药性的策略和确定 DNA 损伤反应的基本机制至关重要。本文重点介绍 PARP 抑制剂的作用机制、耐药的各种原因以及克服 PARP 抑制剂耐药性的策略。
