Pharmacological inhibition of the ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR; also known as FRAP-related protein (FRP1)) has emerged as a promising strategy for cancer treatment that exploits synthetic lethal interactions with proteins involved in DNA damage repair, overcomes resistance to other therapies and enhances antitumour immunity. Multiple novel, potent ATR inhibitors are being tested in clinical trials using biomarker-directed approaches and involving patients across a broad range of solid cancer types; some of these inhibitors have now entered phase III trials. Further insight into the complex interactions of ATR with other DNA replication stress response pathway components and with the immune system is necessary in order to optimally harness the potential of ATR inhibitors in the clinic and achieve hypomorphic targeting of the various ATR functions. Furthermore, a deeper understanding of the diverse range of predictive biomarkers of response to ATR inhibitors and of the intraclass differences between these agents could help to refine trial design and patient selection strategies. Key challenges that remain in the clinical development of ATR inhibitors include the optimization of their therapeutic index and the development of rational combinations with these agents. In this Review, we detail the molecular mechanisms regulated by ATR and their clinical relevance, and discuss the challenges that must be addressed to extend the benefit of ATR inhibitors to a broad population of patients with cancer.

共济失调毛细血管扩张和 Rad3 相关蛋白丝氨酸/苏氨酸激酶（ATR；也称为 FRAP 相关蛋白 (FRP1)）的药理抑制已成为一种有前途的癌症治疗策略，该策略利用与参与 DNA 损伤修复的蛋白质的合成致死相互作用，克服对其他疗法的耐药性并增强抗肿瘤免疫力。多种新型、有效的 ATR 抑制剂正在临床试验中进行测试，使用生物标志物导向的方法，并涉及多种实体癌类型的患者；其中一些抑制剂现已进入 III 期试验。为了在临床中最佳地利用 ATR 抑制剂的潜力并实现各种 ATR 功能的亚效靶向，有必要进一步深入了解 ATR 与其他 DNA 复制应激反应途径成分以及免疫系统的复杂相互作用。此外，更深入地了解 ATR 抑制剂反应的各种预测生物标志物以及这些药物之间的类内差异可能有助于完善试验设计和患者选择策略。ATR抑制剂临床开发中仍然存在的关键挑战包括优化其治疗指数以及开发与这些药物的合理组合。在这篇综述中，我们详细介绍了 ATR 调节的分子机制及其临床相关性，并讨论了将 ATR 抑制剂的益处扩大到广大癌症患者群体所必须解决的挑战。