The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely to enter S phase with increased RS. These cancer cells become more reliant on their S and G2/M checkpoints, making this an attractive anti-cancer target. Targeting ATR is the focus of many oncology drug pipelines with a number of potent, selective ATR inhibitors developed, four (M6620, M4344, AZD6738 and BAY1895344) are currently in clinical development. Here we summarise the pre-clinical data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and novel targeted agents such as PARP inhibitors. We discuss the current clinical trial data and the challenges of taking ATR inhibitors into the clinic and of identifying biomarkers to aid patient selection.

中文翻译：

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将ATR定位为癌症疗法：合成杀伤力和协同组合的新时代？

DNA损伤响应（DDR）机制负责检测DNA损伤，暂停细胞周期并启动DNA修复。共济失调毛细血管扩张症和Rad3相关（ATR）蛋白是DDR核心的关键激酶，负责感测复制应激（RS）并将其信号传导至S和G2 / M检查点以促进修复。在癌症中，G1检查点控制的丧失和驱动复制的致癌基因的激活导致癌细胞更可能进入RS增高的S期。这些癌细胞变得更加依赖于S和G2 / M检查点，这使其成为有吸引力的抗癌靶标。靶向ATR是许多肿瘤药物研发的重点，已开发出许多有效的选择性ATR抑制剂，其中四种（M6620，M4344，AZD6738和BAY1895344）目前正在临床开发中。在这里，我们总结了临床前数据，这些数据支持将ATR抑制剂用作单一疗法，并与化疗，放疗和新型靶向药物（如PARP抑制剂）结合使用。我们讨论了当前的临床试验数据以及将ATR抑制剂带入临床以及识别生物标志物以帮助患者选择的挑战。