Targeting the ATR-CHK1 Axis in Cancer Therapy.
Targeting the ATR-CHK1 Axis in Cancer Therapy.
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DOI：
10.3390/cancers9050041
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发表时间：
2017-04-27
期刊：
影响因子：
5.2
通讯作者：
Curtin NJ
中科院分区：
文献类型：
--
作者：
Rundle S;Bradbury A;Drew Y;Curtin NJ
靶向DNA损伤反应（DDR）是一种新的癌症治疗方法，在肿瘤选择性方面显示出巨大的前景。DDR的关键成分是共济失调毛细血管扩张突变和Rad 3相关（ATR）和检查点激酶1（CHK 1）激酶。这篇综述文章描述了ATR及其主要下游靶点CHK 1在DDR中的作用，以及为什么癌细胞特别依赖于ATR-CHK 1通路，为靶向这些激酶提供了理论基础，并通过遗传操作验证了这一假设。描述了特异性抑制剂的最新发展和使用这些抑制剂不仅作为化学增敏剂和放射增敏剂，而且还作为单一药剂利用肿瘤细胞的特定病理的临床前数据。这些有效和特异性的抑制剂现已进入临床试验，并已获得初步结果。
Targeting the DNA damage response (DDR) is a new therapeutic approach in cancer that shows great promise for tumour selectivity. Key components of the DDR are the ataxia telangiectasia mutated and Rad3 related (ATR) and checkpoint kinase 1 (CHK1) kinases. This review article describes the role of ATR and its major downstream target, CHK1, in the DDR and why cancer cells are particularly reliant on the ATR-CHK1 pathway, providing the rationale for targeting these kinases, and validation of this hypothesis by genetic manipulation. The recent development of specific inhibitors and preclinical data using these inhibitors not only as chemosensitisers and radiosensitisers but also as single agents to exploit specific pathologies of tumour cells is described. These potent and specific inhibitors have now entered clinical trial and early results are presented.