Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

中文翻译：

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PARP和PARG抑制剂在癌症治疗中。

氧化和复制应激是癌细胞基因组不稳定的基础。通过放射疗法和化学疗法放大基因组不稳定性一直是杀死癌细胞的强有力但非选择性的手段。精密医学通过提出选择性靶向癌细胞的概念，彻底改变了癌症治疗方法。聚（ADP-核糖）聚合酶（PARP）抑制剂代表了精确药物的成功实例，因为它是针对DNA损伤反应的首批进入临床的药物。PARP抑制剂可通过合成致死作用作用DNA修复基因中的突变，因此被批准用于治疗BRCA突变的卵巢癌和乳腺癌。PARP抑制剂可通过PARP DNA截留来破坏复制叉，并通过复制应激诱导的有丝分裂灾难诱导细胞死亡。聚（ADP-核糖）糖水解酶（PARG）抑制剂可利用并加剧癌细胞的复制缺陷，并可能在针对具有不同基因组不稳定来源的多种癌症类型中补充PARP抑制剂。在这里，我提供了PARP和PARG抑制的分子机制和细胞后果的概述。我重点介绍了用于癌症治疗的四种PARP抑制剂（奥拉帕尼，鲁卡帕利布，尼拉帕利布和他拉唑帕尼）的临床表现，并讨论了抑制剂敏感性的预测生物标志物，耐药机制以及通过联合疗法克服它们的方法。在这里，我提供了PARP和PARG抑制的分子机制和细胞后果的概述。我重点介绍了用于癌症治疗的四种PARP抑制剂（奥拉帕尼，鲁卡帕利布，尼拉帕利布和他拉唑帕尼）的临床表现，并讨论了抑制剂敏感性的预测生物标志物，耐药机制以及通过联合疗法克服它们的方法。在这里，我提供了PARP和PARG抑制的分子机制和细胞后果的概述。我重点介绍了用于癌症治疗的四种PARP抑制剂（奥拉帕尼，鲁卡帕利布，尼拉帕利布和他拉唑帕尼）的临床表现，并讨论了抑制剂敏感性的预测生物标志物，耐药机制以及通过联合疗法克服它们的方法。