Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy.
Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy.
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DOI：
10.1080/23723556.2015.1012976
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发表时间：
2015-10
影响因子：
2.1
通讯作者：
Vitale I
中科院分区：
文献类型：
--
作者：
Manic G;Obrist F;Sistigu A;Vitale I
共济失调毛细血管扩张症突变丝氨酸/苏氨酸激酶(ATM)/检查点激酶2(CHEK2，最为人所知的CHK2)和ATM和RAD3相关的丝氨酸/苏氨酸激酶(ATR)/CHEK1(最为人所知的CHK1)级联是驱动DNA损伤反应(DDR)的两个主要信号通路，DDR是维持基因组稳定性的关键过程，是阻止肿瘤发生和肿瘤进展的屏障。ATM和/或Chk2的突变和/或缺失在肿瘤中经常发现，并容易导致癌症的发生。相反，ATR-CHK1途径通常在肿瘤中上调，并被认为促进肿瘤生长，尽管一些证据表明，ATR和CHK1也可能表现为单倍体不足的共抑制因子，至少在特定的遗传背景下是这样。ATM-CHK2和ATR-CHK1通路的失活有效地使肿瘤细胞对放疗和化疗敏感。此外，ATR和CHK1抑制剂选择性地杀死那些呈现高水平复制应激、P53(或其他DDR成员)缺乏或上调ATR-CHK1模块的肿瘤细胞。尽管有希望的临床前结果，但ATM、ATR、CHK1和CHK2抑制剂单独或与其他治疗药物联合使用的临床活性尚未得到充分证明。在这项试验观察中，我们概述了ATM-CHK2和ATR-CHK1通路在癌症发生和发展中的作用，并总结了旨在评估基于ATR和CHK1抑制剂的方案的安全性和治疗概况的临床研究结果，这两类化合物是迄今进入临床的唯一两类化合物。
The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors and predispose to cancer development. In contrast, the ATR–CHK1 pathway is often upregulated in neoplasms and is believed to promote tumor growth, although some evidence indicates that ATR and CHK1 may also behave as haploinsufficient oncosuppressors, at least in a specific genetic background. Inactivation of the ATM–CHK2 and ATR–CHK1 pathways efficiently sensitizes malignant cells to radiotherapy and chemotherapy. Moreover, ATR and CHK1 inhibitors selectively kill tumor cells that present high levels of replication stress, have a deficiency in p53 (or other DDR players), or upregulate the ATR–CHK1 module. Despite promising preclinical results, the clinical activity of ATM, ATR, CHK1, and CHK2 inhibitors, alone or in combination with other therapeutics, has not yet been fully demonstrated. In this Trial Watch, we give an overview of the roles of the ATM-CHK2 and ATR-CHK1 pathways in cancer initiation and progression, and summarize the results of clinical studies aimed at assessing the safety and therapeutic profile of regimens based on inhibitors of ATR and CHK1, the only 2 classes of compounds that have so far entered clinics.