Molecular Pathways: Targeting ATR in Cancer Therapy.
Molecular Pathways: Targeting ATR in Cancer Therapy.
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DOI：
10.1158/1078-0432.ccr-15-0479
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发表时间：
2015-11-01
期刊：
影响因子：
--
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Karnitz LM;Zou L
人类ATR基因编码一种由DNA损伤和复制应激激活的激酶，作为检查点信号通路的中心转导。一旦被激活，ATR就会磷酸化多种底物，包括激酶Chk1，以调节细胞周期进程、复制叉稳定性和DNA修复。这些事件在复制应激和DNA损伤的细胞中促进了细胞的存活。因此，有一个诱人的可能性，ATR抑制剂将在治疗上有用，特别是如果它们对肿瘤细胞比正常细胞更有效。事实上，多项研究表明，促进肿瘤发生的改变，如ATM-P53途径的缺陷，结构性癌基因激活，以及获得替代的端粒延长途径，使肿瘤细胞对ATR抑制剂单一治疗和/或增加ATR抑制剂和基因毒性化疗之间的协同作用变得敏感。现在，在发现ATR近20年后，两种高度选择性和强大的ATR抑制剂AZD6738和VX-970正处于早期临床试验阶段，要么作为单一疗法，要么与多种遗传毒性化疗药物联合使用。这些试验将对ATR抑制对人类的影响以及抑制该激酶在治疗人类恶性肿瘤中的潜在作用产生重要的见解。
The human ATR gene encodes a kinase that is activated by DNA damage and replication stress as a central transducer of a checkpoint signaling pathway. Once activated, ATR phosphorylates multiple substrates, including the kinase Chk1, to regulate cell cycle progression, replication fork stability, and DNA repair. These events promote cell survival during replication stress and in cells with DNA damage. Accordingly, there has been the tantalizing possibility that ATR inhibitors would be therapeutically useful, especially if they were more effective in tumor versus normal cells. Indeed, multiple studies have demonstrated that alterations that promote tumorigenesis, such as defects in the ATM-p53 pathway, constitutive oncogene activation, and acquisition of the alternative lengthening of telomeres pathway, render tumor cells sensitive to ATR inhibitor monotherapy and/or increase the synergy between ATR inhibitors and genotoxic chemotherapies. Now, nearly two decades after the discovery of ATR, two highly selective and potent ATR inhibitors, AZD6738 and VX-970, are in early phase clinical trials either as monotherapies or paired with a variety of genotoxic chemotherapies. These trials will generate important insights into the effects of ATR inhibition in humans and the potential role of inhibiting this kinase in the treatment of human malignancies.