BET bromodomain inhibition of MYC-amplified medulloblastoma.
BET bromodomain inhibition of MYC-amplified medulloblastoma.
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DOI：
10.1158/1078-0432.ccr-13-2281
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发表时间：
2014-02-15
期刊：
影响因子：
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通讯作者：
Cho YJ
中科院分区：
文献类型：
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作者：
Bandopadhayay P;Bergthold G;Nguyen B;Schubert S;Gholamin S;Tang Y;Bolin S;Schumacher SE;Zeid R;Masoud S;Yu F;Vue N;Gibson WJ;Paolella BR;Mitra SS;Cheshier SH;Qi J;Liu KW;Wechsler-Reya R;Weiss WA;Swartling FJ;Kieran MW;Bradner JE;Beroukhim R;Cho YJ
myc扩增髓母细胞瘤是一种高致死性肿瘤。BET溴结构域抑制最近被证明可以抑制其他癌症中myc相关的转录活性。化合物JQ1抑制含有BET溴结构域的蛋白，包括BRD4。在这里，我们研究BET溴域靶向治疗myc扩增的髓母细胞瘤。我们评估了遗传和药理学抑制BET bromodomains对已建立和新生成的患者和gemm来源的髓母细胞瘤细胞系和携带MYC或MYCN扩增的异种移植物的增殖、细胞周期和凋亡的影响。我们还评估了JQ1对MYC表达和MYC相关转录活性的影响。我们评估了JQ1在免疫功能低下小鼠原位异种移植物中的体内疗效。用JQ1治疗myc扩增的髓母细胞瘤细胞会降低细胞活力，与G1期阻滞和凋亡相关。我们观察到MYC表达下调，并证实MYC相关转录靶点受到抑制。来自逆转录病毒启动子的外源性MYC表达降低了JQ1对细胞活力的影响，这表明MYC水平的降低有助于JQ1的功能影响。JQ1显著延长myc扩增髓母细胞瘤原位异种移植模型的存活时间（p<0.001）。注射五剂JQ1后，小鼠的异种移植物MYC mRNA的表达降低，增殖指数降低。JQ1抑制髓母细胞瘤中MYC的表达和MYC相关的转录活性，导致髓母细胞瘤细胞活力总体下降。这些临床前研究结果突出了BET溴结构域抑制剂作为治疗myc扩增髓母细胞瘤的新药物的前景。
MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. We evaluated the effects of genetic and pharmacological inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and GEMM-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed down-regulation of MYC expression and confirmed inhibition of MYC-associated transcriptional targets. Exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged survival of orthotopic xenograft models of MYC-amplified medulloblastoma (p<0.001). Xenografts harvested from mice after five doses of JQ1 had reduced expression of MYC mRNA and a reduced proliferative index. JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.