Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
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DOI：
10.1038/s41388-018-0135-1
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发表时间：
2018-05-01
期刊：
影响因子：
8
通讯作者：
Swartling, Fredrik J.
中科院分区：
文献类型：
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作者：
Bolin, Sara;Borgenvik, Anna;Swartling, Fredrik J.
髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。 MYC 基因经常被扩增，并与 MB 的不良预后相关。 BET 溴结构域识别乙酰化赖氨酸残基，通常促进和维持 MYC 转录。进一步已知某些细胞周期蛋白依赖性激酶 (CDK) 支持肿瘤细胞中 MYC 的稳定。在本报告中，分别使用 BET 溴结构域抑制和 CDK2 抑制联合靶向 MYC 表达和 MYC 稳定化，从而抑制 MB 细胞。这种联合治疗具有协同作用，导致细胞周期停滞和大量细胞凋亡。使用 RNA-Seq 分析发现了这种联合 MYC 阻断带来的直接转录变化，并且与我们在第 3 组 MB 的 MYCN 诱导动物模型中用多西环素关闭 MYCN 时 MYC 靶基因表达的变化显着相似。此外，与单药治疗相比，联合治疗显着延长了原位移植的具有 MYC 扩增的人类 3 MB 组的生存期。我们的数据表明，CDK2 和 BET 溴结构域的双重抑制可以成为抑制 MYC 驱动的癌症的新治疗方法。
Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.