细胞演化出了一种复杂的生化途径网络，被称为DNA损伤反应（DDR），以防止有害突变遗传给后代。DDR将DNA修复与细胞周期检查点激活和其他全局细胞反应协调在一起。编码DDR因子的基因在癌症中经常发生突变，导致基因组不稳定性，这是许多肿瘤的内在特征，是它们能够生长、转移和应对造成DNA损伤的治疗手段（如放疗）的能力的基础。我们可以更深入地了解基因DDR消失如何影响治疗反应的情况是，对于突变BRCA1或BRCA2的肿瘤。由于同源重组DNA修复受损，这些肿瘤依赖于替代修复机制，并且容易受到聚（ADP核糖）聚合酶（PARP）的化学抑制剂的影响，PARP具体杀死同源重组缺陷的癌细胞，并已成为定向癌症治疗的范例。现在明确的是，许多其他DDR基因之间存在合成致死（synthetic-lethal）关系。重要的是，其中一些相互作用可以在临床上利用，以针对变得抗药的PARP抑制剂的肿瘤。在这篇评论中，我们讨论使用小分子抑制剂失活DDR的最先进策略，并强调当前在临床中评估的那些化合物。©2022 Springer Nature Limited。

Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Genes encoding DDR factors are frequently mutated in cancer, causing genomic instability, an intrinsic feature of many tumours that underlies their ability to grow, metastasize and respond to treatments that inflict DNA damage (such as radiotherapy). One instance where we have greater insight into how genetic DDR abrogation impacts on therapy responses is in tumours with mutated BRCA1 or BRCA2. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms and are susceptible to chemical inhibitors of poly(ADP-ribose) polymerase (PARP), which specifically kill homologous recombination-deficient cancer cells, and have become a paradigm for targeted cancer therapy. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. In this Review, we discuss state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlight those compounds currently being evaluated in the clinic.© 2022. Springer Nature Limited.