文章：

靶向癌症中的DNA损伤反应途径

Targeting DNA damage response pathways in cancer

原文发布日期：2022-12-05

DOI: 10.1038/s41568-022-00535-5

类型: Review Article

开放获取: 否

英文摘要：

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.

摘要翻译： 

细胞演化出了一套复杂的生化通路网络——即DNA损伤反应系统（DDR），以防止有害突变遗传给后代。DDR系统通过协调DNA修复与细胞周期检查点激活及其他全局细胞反应来实现这一功能。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（许多肿瘤的内在特征），这种特性正是肿瘤能够生长、转移并应对DNA损伤治疗（如放疗）的基础。以BRCA1或BRCA2基因突变的肿瘤为例，我们能更深入理解遗传性DDR缺陷如何影响治疗反应。由于同源重组DNA修复功能受损，这些肿瘤依赖替代修复机制，因此对聚ADP核糖聚合酶（PARP）化学抑制剂敏感。这类抑制剂能特异性杀死同源重组缺陷的癌细胞，已成为靶向癌症治疗的典范。目前明确的是，DDR基因之间还存在许多其他合成致死关系。关键在于，这些相互作用中有一部分可在临床中用于靶向已对PARP抑制产生耐药性的肿瘤。本综述将探讨使用小分子抑制剂失活DDR系统的最新策略，并重点介绍当前处于临床评估阶段的化合物。

原文链接：

Targeting DNA damage response pathways in cancer