ATR/CHK1 inhibitors and cancer therapy.
ATR/CHK1 inhibitors and cancer therapy.
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DOI：
10.1016/j.radonc.2017.09.043
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Qiu Z;Oleinick NL;Zhang J
细胞周期检查点蛋白共济失调-毛细血管扩张-突变-和-Rad 3-相关激酶（ATR）及其主要下游效应物检查点激酶1（CHK 1）防止具有受损或不完全复制的DNA的细胞在受到DNA损伤剂（例如放射疗法（RT）或化学治疗药物）攻击时进入有丝分裂，所述DNA损伤剂是治疗癌症的主要方式。这种调节在具有缺陷的G1检查点的细胞中特别明显，这是由于p53突变导致的癌细胞的共同特征。此外，ATR和/或CHK 1通过抑制过度的原点放电来抑制复制应激（RS），特别是在具有活化的癌基因的细胞中。ATR/CHK 1的这些功能使其成为理想的治疗靶点。ATR/CHK 1抑制剂已经开发出来，目前在临床前和临床研究中作为单一药物或与放射治疗或各种遗传毒性化疗配对使用。本文就ATR和CHK 1抑制剂的研究进展作一综述。我们还讨论了ATR和CHK 1抑制诱导细胞杀伤在存在或不存在外源性DNA损伤剂，如RT和化疗药物的潜在机制。最后，我们讨论了ATR/CHK 1的抑制和其他DNA损伤反应（DDR）途径/基因的缺陷之间的合成致死性相互作用。
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.
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