Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's, Hospital Colorado, Aurora, CO, USA.
Cell Rep. 2021 Apr 27;35(4):109013. doi: 10.1016/j.celrep.2021.109013.
MYC-driven medulloblastoma is a major therapeutic challenge due to frequent metastasis and a poor 5-year survival rate. MYC gene amplification results in transcriptional dysregulation, proliferation, and survival of malignant cells. To identify therapeutic targets in MYC-amplified medulloblastoma, we employ a CRISPR-Cas9 essentiality screen targeting 1,140 genes. We identify CDK7 as a mediator of medulloblastoma tumorigenesis. Using chemical inhibitors and genetic depletion, we observe cessation of tumor growth in xenograft mouse models and increases in apoptosis. The results are attributed to repression of a core set of MYC-driven transcriptional programs mediating DNA repair. CDK7 inhibition alters RNA polymerase II (RNA Pol II) and MYC association at DNA repair genes. Blocking CDK7 activity sensitizes cells to ionizing radiation leading to accrual of DNA damage, extending survival and tumor latency in xenograft mouse models. Our studies establish the selective inhibition of MYC-driven medulloblastoma by CDK7 inhibition combined with radiation as a viable therapeutic strategy.
由于频繁转移和 5 年生存率低，MYC 驱动的髓母细胞瘤是一个主要的治疗挑战。MYC 基因扩增导致恶性细胞的转录失调、增殖和存活。为了确定 MYC 扩增髓母细胞瘤的治疗靶点，我们采用 CRISPR-Cas9 对 1140 个基因进行了必需性筛选。我们鉴定出 CDK7 是髓母细胞瘤发生的介质。通过化学抑制剂和基因耗竭，我们观察到异种移植小鼠模型中的肿瘤生长停止和细胞凋亡增加。结果归因于抑制一组介导 DNA 修复的核心 MYC 驱动转录程序。CDK7 抑制改变了 RNA 聚合酶 II（RNA Pol II）和 MYC 在 DNA 修复基因上的结合。阻断 CDK7 活性使细胞对电离辐射敏感，导致 DNA 损伤积累，延长异种移植小鼠模型中的存活时间和肿瘤潜伏期。我们的研究确立了 CDK7 抑制联合辐射选择性抑制 MYC 驱动的髓母细胞瘤作为一种可行的治疗策略。
