Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
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DOI：
10.1038/s41467-019-10307-9
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发表时间：
2019-06-03
影响因子：
16.6
通讯作者：
Beroukhim, Rameen
中科院分区：
文献类型：
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作者：
Bandopadhayay, Pratiti;Piccioni, Federica;Beroukhim, Rameen
BET-布罗莫结构域抑制（BETi）已显示出用于MYC扩增的髓母细胞瘤的临床前前景。然而，其作用机制以及最终的耐药性机制尚未得到充分界定。在这里，使用表达谱分析、基因组规模的CRISPR/Cas9介导的功能丧失和ORF/cDNA驱动的拯救筛选以及基于细胞的自发抗性模型的组合，我们将bHLH/同源框转录因子和细胞周期调节因子鉴定为介导BETi反应和抗性的关键基因。获得药物耐受性的细胞表现出更多的神经元分化的细胞状态和谱系特异性bHLH/同源框转录因子的表达。然而，它们不终末分化，维持CCND 2的表达，并继续通过S期循环。此外，CDK 4/CDK 6抑制延迟抗性的获得。因此，我们的数据提供了关于BETi效应和耐药性出现的机制的见解，并支持联合细胞周期抑制剂与BETi在MYC扩增的髓母细胞瘤中的治疗用途。
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.