DNA Damage Response Biology, Bioscience Oncology IMED Biotech Unit, AstraZeneca, Cambridge CB4 0WG, UK.
DNA Damage Response Biology, Bioscience Oncology IMED Biotech Unit, AstraZeneca, Cambridge CB4 0WG, UK.
Pharmacol Ther. 2018 Aug;188:155-167. doi: 10.1016/j.pharmthera.2018.03.005. Epub 2018 Mar 24.
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.
许多用于癌症治疗的传统化疗药物通过造成 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伤的影响，从而导致不必要的毒性。相比之下，靶向治疗方法旨在特异性地消除癌细胞，但对健康组织的影响较小。已经开发出了针对复制应激反应 (RSR) 的新疗法，这是更广泛的 DNA 损伤反应的一个分支，专门处理正常 DNA 复制程序的干扰。不同的制药公司已经开发出了 RSR 激酶 ATR、CHK1 和 WEE1 的抑制剂，这些抑制剂目前处于不同的临床开发阶段。在这里，我们将回顾 RSR 在分子水平上的工作原理、针对它的原理是什么，以及根据体外和体内临床前研究支持的患者选择和联合治疗，我们如何设想它在临床上的最佳应用。
