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Oncogene. 2019 May;38(20):3932-3945. doi: 10.1038/s41388-019-0701-1. Epub 2019 Jan 28.

THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer.

Author information

1
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
2
Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
4
Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
5
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
6
Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
7
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. liweiwang@shsmu.edu.cn.
8
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. liweiwang@shsmu.edu.cn.
9
Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. yujietang@shsmu.edu.cn.
10
State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingxue@sjtu.edu.cn.

Abstract

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.

PMID:
30692639
DOI:
10.1038/s41388-019-0701-1
[Indexed for MEDLINE]

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