THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer
THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer
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THZ1 揭示了胰腺癌中 CDK7 依赖性转录成瘾。
DOI：
10.1038/s41388-019-0701-1
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发表时间：
2019-05-16
期刊：
影响因子：
8
通讯作者：
Xue, Jing
中科院分区：
文献类型：
--
作者：
Lu, Ping;Geng, Jing;Xue, Jing
胰腺导管腺癌(PDAC)是一种高死亡率的致命性恶性肿瘤。缺乏有效的治疗方法使得新的治疗发现成为PDAC研究的迫切需求。通过筛选表观遗传相关化合物文库，我们确定CDK7的共价抑制剂THZ1是一个有希望的候选者。使用多个长期建立的和患者来源的PDAC细胞系(PDC)来验证THZ1的体外疗效。此外，采用患者来源的异种移植(PDX)模型和PDAC的动物模型检测THZ1的体内疗效。此外，通过RNA-Seq分析揭示了THZ1处理的分子机制。最后，对对THZ1具有原发耐药或获得性耐药的PDAC细胞株进行研究，以探讨THZ1敏感性的可能机制。在多种临床前模型中，抑制CDK7被确定为PDAC进展的一种选择性和有效的治疗策略。机制分析表明，CDK7抑制导致基因转录明显下调，优先抑制有丝分裂细胞周期和核因子-kappaB信号相关转录。研究发现，MYC转录参与了PDAC细胞对CDK7抑制的敏感性。总之，在PDAC中识别依赖CDK7的转录成瘾提供了一种针对高侵袭性胰腺癌的有效治疗策略。
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high mortality. Lack of effective treatment makes novel therapeutic discovery an urgent demand in PDAC research. By screening an epigenetic-related compound library, we identified THZ1, a covalent inhibitor of CDK7, as a promising candidate. Multiple long-established and patient-derived PDAC cell lines (PDC) were used to validate the efficacy of THZ1 in vitro. In addition, patient-derived xenograft (PDX) models and animal models of PDAC were utilized for examining THZ1 efficacy in vivo. Furthermore, RNA-Seq analyse was performed to reveal the molecular mechanism of THZ1 treatment. Finally, PDAC cell lines with primary or acquired resistance to THZ1 were investigated to explore the potential mechanism of THZ1 susceptibility. CDK7 inhibition was identified as a selective and potent therapeutic strategy for PDAC progression in multiple preclinical models. Mechanistic analyses revealed that CDK7 inhibition led to a pronounced downregulation of gene transcription, with a preferential repression of mitotic cell cycle and NF-kappa B signaling-related transcripts. MYC transcriptional was found to be involved in susceptibility of PDAC cells to CDK7 inhibition. In conclusion, Identification of CDK7-dependent transcriptional addiction in PDACs provides a potent therapeutic strategy that targets highly aggressive pancreatic cancer.