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THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer

细胞周期蛋白依赖激酶7 癌症研究 生物 下调和上调 转录组 体内 细胞培养 癌症 基因 基因表达 细胞周期 遗传学 细胞周期蛋白依赖激酶2
作者
Ping Lu,Jing Geng,Lei Zhang,Yu Wang,Ningning Niu,Yuan Fang,Fang Liu,Juanjuan Shi,Zhigang Zhang,Yongwei Sun,Liwei Wang,Yujie Tang,Jing Xue
出处
期刊:Oncogene [Springer Nature]
卷期号:38 (20): 3932-3945 被引量:57
标识
DOI:10.1038/s41388-019-0701-1
摘要

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-κB 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.
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