WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells
WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells
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DOI：
10.1038/onc.2012.153
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发表时间：
2013-03-14
期刊：
影响因子：
8
通讯作者：
de Alava, E.
中科院分区：
文献类型：
--
作者：
Mackintosh, C.;Garcia-Dominguez, D. J.;de Alava, E.
尤文肉瘤是一种儿童和青壮年侵袭性骨和软组织肿瘤，寻找有效的新靶向治疗方法势在必行。在这里，我们报告了一项深入的临床前研究，研究中的剔除泛素连接酶(CRL)抑制剂MLN4924在ES中，因为我们最近证明了CRL成分在ES发病机制中的意义。首先，我们的结果支持ES细胞对MLN4924生长抑制的高度敏感性，无论是在体外(14个ES细胞系测试，IC50中值=81 NM)还是在肿瘤移植瘤中(皮下注射60 mg/kg BID，肿瘤消退，n=9)。第二，我们报道了MLN4924在ES细胞中的双重作用机制：当大范围的MLN4924浓度(类似于30-300 nM)触发G2期停滞时，只能通过抑制或耗尽WEE1激酶来挽救，饱和剂量的药物(>；300 nM)会导致S期进展延迟，伴随着CDK2-Cyclin E和CDK2-Cyclin A相对水平的失衡(第一种水平的积累和后者的耗尽)。细胞周期晚期S期细胞核中CDC6的异常存在证实了CDK2-Cyclin A特异性功能的丧失。值得注意的是，其他已探索的机制(P27积累和DNA损伤信号通路)被发现无法解释MLN4924的影响，这加强了我们发现的特异性，并表明一些CRL底物缺乏功能，这些底物是在对MLN4924的反应中积累的。这项研究为临床试验提供了理论基础，并为更好地了解这种有前途的抗肿瘤药物提供了分子机制。Oncogene(2013年)32,1441-1451；doi：10.1038/onc.2012.153；2012年5月28日在线发布
Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of children and young adults in which finding effective new targeted therapies is imperative. Here, we report an in-depth preclinical study of the investigational cullin-RING ubiquitin ligase (CRL) inhibitor MLN4924 in ES, as we have recently demonstrated the implication of a CRL component in the ES pathogenesis. First, our results support a high sensitivity of ES cells to MLN4924 growth inhibition both in vitro (14 ES cell lines tested, median IC50 = 81 nM) and in tumor xenografts (tumor regression achieved with 60 mg/kg BID, subcutaneously, n = 9). Second, we report a dual mechanism of action of MLN4924 in ES cells: while a wide range of MLN4924 concentrations (similar to 30-300 nM) trigger a G2 arrest that can only be rescued by WEE1 kinase inhibition or depletion, saturating doses of the drug (>300 nM) cause a delay in S-phase progression concomitant with unbalanced CDK2-Cyclin E and CDK2-Cyclin A relative levels (accumulation of the first and depletion of the latter). The aberrant presence of CDC6 in the nucleus at late S-phase cell cycle stage confirmed the loss of CDK2-Cyclin A-specific functions. Remarkably, other mechanisms explored (P27 accumulation and DNA damage signaling pathways) were found unable to explain MLN4924 effects, strengthening the specificity of our findings and suggesting the absence of functionality of some CRL substrates accumulated in response to MLN4924. This study renders a rationale for clinical trials and contributes molecular mechanisms for a better understanding of this promising antitumoral agent. Oncogene (2013) 32, 1441-1451; doi:10.1038/onc.2012.153; published online 28 May 2012