Many conventional chemotherapies used in cancer treatment exert their effect by inflicting DNA damage. Highly proliferative tissues, as well as tumour cells, are particularly vulnerable to this damage resulting in unwanted toxicities. In contrast, a targeted therapeutic approach has the aim of specifically eliminating cancer cells but with a reduced effect on healthy tissue. New therapies have been developed that target the replication stress response (RSR), a branch of the broader DNA damage response that specifically deals with interferences of the normal DNA replication program. Different pharmaceutical companies have developed inhibitors of the RSR kinases ATR, CHK1 and WEE1, which are currently at different phases of clinical development. Here, we review how the RSR works at the molecular level, what is the rationale for its targeting, and how we envisage its best use in the clinic, based on patient selection and combination therapies supported by in vitro and in vivo preclinical studies.

用于癌症治疗的许多常规化学疗法通过造成DNA损伤来发挥作用。高度增殖的组织以及肿瘤细胞特别容易受到这种损害，从而导致有害的毒性。相反，靶向治疗方法的目的是特异性消除癌细胞，但对健康组织的作用降低。已经开发出针对复制应激反应（RSR）的新疗法，后者是更广泛的DNA损伤反应的一个分支，专门应对正常DNA复制程序的干扰。不同的制药公司已经开发了RSR激酶ATR，CHK1和WEE1的抑制剂，这些抑制剂目前处于临床开发的不同阶段。在这里，我们回顾了RSR在分子水平上的工作原理，以及针对它的针对性是什么，