Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis
Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis
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DOI：
10.1172/jci122622
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发表时间：
2019-03-01
影响因子：
15.9
通讯作者：
Gamper, Armin M.
中科院分区：
文献类型：
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作者：
Bukhari, Amirali B.;Lewis, Cody W.;Gamper, Armin M.
我们使用癌基因诱导的DNA损伤的癌症内在属性作为条件合成致死方法的基础。为了靶向癌细胞适应遗传毒性应激的重要机制，从而实现癌细胞特异性杀伤，我们联合抑制激酶ATR和Wee 1。Wee 1调节细胞周期进程，而ATR是DNA损伤反应中的顶端激酶。在原位乳腺癌模型中，生物可利用的ATR和Wee 1抑制剂的组合的肿瘤选择性合成致死性导致肿瘤缓解并抑制转移，副作用最小。ATR和Wee 1抑制在癌症干细胞中比在大量癌细胞中具有更高的协同效应，弥补了癌症干细胞对单个药物的较低敏感性。从机制上讲，联合治疗导致具有未修复或复制不足的DNA的细胞进入有丝分裂，导致有丝分裂灾难。由于这些ATR和Wee 1抑制剂已经进入I/II期临床试验，这些知识很快就会转化为临床，特别是当我们证明联合治疗针对广泛的肿瘤细胞时。特别是Wee 1/ATR联合抑制的抗转移作用和ATR抑制剂与Chk 1抑制剂相比的低毒性具有巨大的临床潜力。
We used the cancer-intrinsic property of oncogene-induced DNA damage as the base for a conditional synthetic lethality approach. To target mechanisms important for cancer cell adaptation to genotoxic stress and thereby to achieve cancer cell-specific killing, we combined inhibition of the kinases ATR and Wee1. Wee1 regulates cell cycle progression, whereas ATR is an apical kinase in the DNA-damage response. In an orthotopic breast cancer model, tumor-selective synthetic lethality of the combination of bioavailable ATR and Wee1 inhibitors led to tumor remission and inhibited metastasis with minimal side effects. ATR and Wee1 inhibition had a higher synergistic effect in cancer stem cells than in bulk cancer cells, compensating for the lower sensitivity of cancer stem cells to the individual drugs. Mechanistically, the combination treatment caused cells with unrepaired or under-replicated DNA to enter mitosis leading to mitotic catastrophe. As these inhibitors of ATR and Wee1 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic, especially as we showed that the combination treatment targets a wide range of tumor cells. Particularly, the antimetastatic effect of combined Wee1/ATR inhibition and the low toxicity of ATR inhibitors compared with Chk1 inhibitors have great clinical potential.