Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.

针对 DNA 损伤反应 (DDR) 的抗癌药物通过合成致死机制利用该途径中的遗传或功能缺陷。例如，癌细胞中的同源重组 (HR) 修复缺陷是通过BRCA1 、 BRCA2或范可尼贫血/BRCA 途径中其他基因的遗传或获得性突变而出现的，并且这些肿瘤已被证明对同源重组 (HR) 修复的抑制剂特别敏感。碱基切除修复 (BER) 蛋白聚 (ADP-核糖) 聚合酶 (PARP)。最近的工作已经确定了 DNA 修复的其他基因组和功能测定，为这些靶向治疗提供了新的预测和药效生物标志物。在这里，我们研究了针对 DNA 修复的选择性药物的开发，包括 PARP 抑制剂； DNA 损伤激酶共济失调毛细血管扩张症和 Rad3 相关 (ATR)、CHK1、WEE1 和共济失调毛细血管扩张突变 (ATM) 的抑制剂；以及经典非同源末端连接（cNHEJ）和替代末端连接（Alt EJ）的抑制剂。我们还回顾了指导这些药物使用的生物标志物以及当前这些疗法的临床试验。