Sundar Raghav, Brown Jessica, Ingles Russo Alvaro, Yap Timothy A
Drug Development Unit, Royal Marsden Hospital, London, UK; Department of Haematology-Oncology, National University Health System, Singapore.
Drug Development Unit, Royal Marsden Hospital, London, UK.
Curr Probl Cancer. 2017 Jul-Aug;41(4):302-315. doi: 10.1016/j.currproblcancer.2017.05.002. Epub 2017 May 17.
DNA damage occurs continually through various intrinsic and extrinsic mechanisms such as ultraviolet radiation, smoking, reactive oxygen species, and errors during replication. The cellular DNA damage response (DDR) comprises signaling networks that regulate a spectrum of processes, including cell cycle progression, which enable DNA repair to occur. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and rad3-related (ATR) kinase are 2 key regulators of the DDR cell cycle checkpoints. ATR plays an essential role in the repair of replication-associated DNA damage, while ATM is activated by DNA double-strand breaks. The investigation of cell cycle checkpoint signaling through ATR and ATM, as well as the relevant pathways involved in oncogenesis and cancer progression, has led to the discovery and development of potent and selective ATR inhibitors (ATRi). Preclinical data have demonstrated that ATR inhibition leads to tumor synthetic lethality in specific molecular contexts, and it exhibits synergy in combination with different antitumor therapies, including chemotherapy, radiotherapy, and poly(ADP-ribose) polymerase inhibitors. ATRi are now being assessed in early-phase clinical trials as single agents and in combinatorial regimens, including platinum and other chemotherapies, radiotherapy, poly(ADP-ribose) polymerase inhibitors, and immune checkpoint inhibitors. This article details the preclinical biology leading to the discovery and development of novel ATRi and discusses the rationale for monotherapy and combination antitumor strategies. We focus on the clinical development of ATRi and discuss the progress made in identifying putative predictive biomarkers of response for patient selection, such as p53, ATM, ARID1A, and other DDR aberrations.
DNA损伤通过各种内在和外在机制持续发生，如紫外线辐射、吸烟、活性氧以及复制过程中的错误。细胞DNA损伤反应（DDR）由调节一系列过程的信号网络组成，包括细胞周期进程，从而使DNA修复得以发生。共济失调毛细血管扩张症突变基因（ATM）和共济失调毛细血管扩张症突变且与rad3相关基因（ATR）激酶是DDR细胞周期检查点的两个关键调节因子。ATR在复制相关DNA损伤的修复中起重要作用，而ATM由DNA双链断裂激活。对通过ATR和ATM的细胞周期检查点信号传导以及肿瘤发生和癌症进展中涉及的相关途径的研究，已导致发现并开发出强效且选择性的ATR抑制剂（ATRi）。临床前数据表明，在特定分子背景下，ATR抑制会导致肿瘤合成致死，并且它与不同的抗肿瘤疗法联合使用时表现出协同作用，包括化疗、放疗以及聚（ADP - 核糖）聚合酶抑制剂。目前，ATRi正在早期临床试验中作为单一药物以及在联合治疗方案中进行评估，联合治疗方案包括铂类和其他化疗、放疗、聚（ADP - 核糖）聚合酶抑制剂以及免疫检查点抑制剂。本文详细介绍了导致新型ATRi发现和开发的临床前生物学，并讨论了单药治疗和联合抗肿瘤策略的基本原理。我们专注于ATRi的临床开发，并讨论在确定用于患者选择的假定预测生物标志物（如p53、ATM、ARID1A和其他DDR异常）方面取得的进展。
