CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo
CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo
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DOI：
10.3324/haematol.2013.093187
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发表时间：
2014-04-01
期刊：
影响因子：
10.1
通讯作者：
Tibes, Raoul
中科院分区：
文献类型：
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作者：
Chaudhuri, Leena;Vincelette, Nicole D.;Tibes, Raoul
需要针对新的分子脆弱性的新组合来改善急性髓性白血病患者的结局。我们最近发现WEE 1激酶是白血病的一个新靶点。为了鉴定WEE 1抑制的合成致死基因，我们在WEE 1抑制剂MK 1775同时治疗期间针对细胞周期和DNA修复基因进行了短干扰RNA筛选。CHK 1和ATR，编码两个复制检查点激酶的基因，是其中沉默增强WEE 1抑制的效果最多的基因，而CDK 2短干扰RNA拮抗MK 1775的效果。基于这一观察结果，我们研究了MK 1775与CHK 1、ATR和细胞周期蛋白依赖性激酶的选择性小分子抑制剂组合的影响。CHK 1抑制剂MK 8776使急性髓性白血病细胞系和原发性白血病标本对MK 1775体外致敏，而在正常髓性祖细胞中观察到MK 1775/MK 8776组合的较小作用。ATR抑制剂VE-821同样增强MK 1775的抗增殖作用，而细胞周期蛋白依赖性激酶抑制剂roscovitine拮抗MK 1775。进一步的研究表明，MK 8776增强了急性白血病细胞系和离体中MK 1775介导的ATR/CHK 1通路的激活。这些结果表明，MK 1775/MK 8776联合细胞周期检查点干扰作为急性髓性白血病的潜在治疗方法值得进一步研究。
Novel combinations targeting new molecular vulnerabilities are needed to improve the outcome of patients with acute myeloid leukemia. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a short interfering RNA screen directed against cell cycle and DNA repair genes during concurrent treatment with the WEE1 inhibitor MK1775. CHK1 and ATR, genes encoding two replication checkpoint kinases, were among the genes whose silencing enhanced the effects of WEE1 inhibition most, whereas CDK2 short interfering RNA antagonized MK1775 effects. Building on this observation, we examined the impact of combining MK1775 with selective small molecule inhibitors of CHK1, ATR and cyclin-dependent kinases. The CHK1 inhibitor MK8776 sensitized acute myeloid leukemia cell lines and primary leukemia specimens to MK1775 ex vivo, whereas smaller effects were observed with the MK1775/MK8776 combination in normal myeloid progenitors. The ATR inhibitor VE-821 likewise enhanced the antiproliferative effects of MK1775, whereas the cyclin-dependent kinase inhibitor roscovitine antagonized MK1775. Further studies showed that MK8776 enhanced MK1775-mediated activation of the ATR/CHK1 pathway in acute leukemia cell lines and ex vivo. These results indicate that combined cell cycle checkpoint interference with MK1775/MK8776 warrants further investigation as a potential treatment for acute myeloid leukemia.