Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, USA.
Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, USA.
Radiother Oncol. 2018 Mar;126(3):450-464. doi: 10.1016/j.radonc.2017.09.043. Epub 2017 Oct 18.
The cell cycle checkpoint proteins ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (CHK1) prevent the entry of cells with damaged or incompletely replicated DNA into mitosis when the cells are challenged by DNA damaging agents, such as radiation therapy (RT) or chemotherapeutic drugs, that are the major modalities to treat cancer. This regulation is particularly evident in cells with a defective G1 checkpoint, a common feature of cancer cells, due to p53 mutations. In addition, ATR and/or CHK1 suppress replication stress (RS) by inhibiting excess origin firing, particularly in cells with activated oncogenes. Those functions of ATR/CHK1 make them ideal therapeutic targets. ATR/CHK1 inhibitors have been developed and are currently used either as single agents or paired with radiotherapy or a variety of genotoxic chemotherapies in preclinical and clinical studies. Here, we review the status of the development of ATR and CHK1 inhibitors. We also discuss the potential mechanisms by which ATR and CHK1 inhibition induces cell killing in the presence or absence of exogenous DNA damaging agents, such as RT and chemotherapeutic agents. Lastly, we discuss synthetic lethality interactions between the inhibition of ATR/CHK1 and defects in other DNA damage response (DDR) pathways/genes.
细胞周期检查点蛋白共济失调毛细血管扩张突变和 Rad3 相关激酶（ATR）及其主要下游效应物检查点激酶 1（CHK1）可防止细胞在受到 DNA 损伤剂（如放射治疗（RT）或化学疗法药物）的挑战时进入有丝分裂，这些药物是治疗癌症的主要方式。由于 p53 突变，这种调节在具有缺陷 G1 检查点的细胞中尤为明显，这是癌细胞的共同特征。此外，ATR 和/或 CHK1 通过抑制过多起始点的激活来抑制复制应激（RS），特别是在激活致癌基因的细胞中。ATR/CHK1 的这些功能使其成为理想的治疗靶点。已经开发出 ATR/CHK1 抑制剂，并在临床前和临床试验中单独使用或与放射治疗或多种遗传毒性化学疗法联合使用。在这里，我们回顾了 ATR 和 CHK1 抑制剂的发展状况。我们还讨论了在存在或不存在外源性 DNA 损伤剂（如 RT 和化学疗法药物）的情况下，ATR 和 CHK1 抑制诱导细胞杀伤的潜在机制。最后，我们讨论了 ATR/CHK1 抑制与其他 DNA 损伤反应（DDR）途径/基因缺陷之间的合成致死性相互作用。
