Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma.
Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma.
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DOI：
10.3389/fonc.2021.773186
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发表时间：
2021
影响因子：
4.7
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Gao Y;Volegova M;Nasholm N;Das S;Kwiatkowski N;Abraham BJ;Zhang T;Gray NS;Gustafson C;Krajewska M;George RE
细胞周期蛋白依赖性激酶（CDK）在RNA聚合酶II（Pol II）介导的基因转录中具有关键作用，正在成为癌症的治疗靶点。我们之前已经表明，THZ 1，一种CDKs 7/12/13的共价抑制剂，通过下调超级增强子相关的转录上调，导致MYCN扩增的神经母细胞瘤的细胞毒性。在这里，我们确定了YKL-5-124的作用，YKL-5-124是一种新型共价抑制剂，对神经母细胞瘤细胞中的CDK 7具有更高的选择性。我们在MYCN扩增和非扩增的神经母细胞瘤细胞中单独测试了YKL-5-124，并在细胞系和动物模型中与其他抑制剂组合。分析细胞活力、靶验证、对细胞周期和转录的影响。用YKL-5-124抑制CDK 7没有导致显著的细胞死亡，但导致异常的细胞周期进展，特别是在MYCN扩增的细胞中。与THZ 1不同，YKL-5-124对Pol II C-末端结构域磷酸化的影响最小，但显著抑制CDK 1和CDK 2细胞周期激酶的磷酸化。将YKL-5-124与BRD 4抑制剂JQ 1组合导致协同细胞毒性。与对BRD 4抑制的抗性相关的独特MYCN基因表达特征被该组合抑制。YKL-5-124和JQ 1之间的协同作用在神经母细胞瘤的细胞系和患者来源的异种移植小鼠模型中转化为显著的肿瘤消退。CDK 7和BRD 4抑制的组合为神经母细胞瘤提供了一种治疗选择，并表明添加YKL-5-124可以改善JQ 1的治疗功效并延迟对BRD 4抑制的抗性。
Cyclin-dependent kinases (CDKs) that have critical roles in RNA polymerase II (Pol II)-mediated gene transcription are emerging as therapeutic targets in cancer. We have previously shown that THZ1, a covalent inhibitor of CDKs 7/12/13, leads to cytotoxicity in MYCN-amplified neuroblastoma through the downregulation of super-enhancer-associated transcriptional upregulation. Here we determined the effects of YKL-5-124, a novel covalent inhibitor with greater selectivity for CDK7 in neuroblastoma cells. We tested YKL-5-124 in MYCN-amplified and nonamplified neuroblastoma cells individually and in combination with other inhibitors in cell line and animal models. Cell viability, target validation, effects on cell cycle and transcription were analyzed. CDK7 inhibition with YKL-5-124 did not lead to significant cell death, but resulted in aberrant cell cycle progression especially in MYCN-amplified cells. Unlike THZ1, YKL-5-124 had minimal effects on Pol II C-terminal domain phosphorylation, but significantly inhibited that of the CDK1 and CDK2 cell cycle kinases. Combining YKL-5-124 with the BRD4 inhibitor JQ1 resulted in synergistic cytotoxicity. A distinct MYCN-gene expression signature associated with resistance to BRD4 inhibition was suppressed with the combination. The synergy between YKL-5-124 and JQ1 translated into significant tumor regression in cell line and patient-derived xenograft mouse models of neuroblastoma. The combination of CDK7 and BRD4 inhibition provides a therapeutic option for neuroblastoma and suggests that the addition of YKL-5-124 could improve the therapeutic efficacy of JQ1 and delay resistance to BRD4 inhibition.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
FISHER, RP;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
10.5
作者：
Rimel JK;Poss ZC;Erickson B;Maas ZL;Ebmeier CC;Johnson JL;Decker TM;Yaron TM;Bradley MJ;Hamman KB;Hu S;Malojcic G;Marineau JJ;White PW;Brault M;Tao L;DeRoy P;Clavette C;Nayak S;Damon LJ;Kaltheuner IH;Bunch H;Cantley LC;Geyer M;Iwasa J;Dowell RD;Bentley DL;Old WM;Taatjes DJ
通讯作者：
Taatjes DJ