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THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer

Oncogene volume 38, pages 3932–3945 (2019)Cite this article

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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.

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Author contributions

J.X., P.L., and Y.T. designed experiment, interpreted data, and wrote the manuscript; P.L., J.G., and L.Z. performed most of the experiments; Y.W., N.N., and F.L. assisted in some experiments; Y.F., Y.-W.S., and Z.-G.Z. provided the key materials; J.X., Y.T. and L.-W.W. provided the overall guide.

Funding

This work was supported by the Program for professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning No.TP2015007 to J.X., TP2015017 to Y.T.), National Natural Science Foundation of China (81702938 and 81770628 to J.X.; 81572761 and 81772655 to Y.T.), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support No.20161312 (J.X.), The Recruitment Program of Global Experts of China (National 1000-Youth Talents Program to Y.T.), Shanghai Rising-Star Program (Y.T.).

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  1. These authors contributed equally: Ping Lu, Jing Geng, Lei Zhang

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Ping Lu, Jing Geng, Ningning Niu, Juanjuan Shi & Jing Xue

  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

    Lei Zhang, Fang Liu & Yujie Tang

  3. Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yu Wang & Li-Wei Wang

  4. Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yuan Fang

  5. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Zhi-Gang Zhang & Li-Wei Wang

  6. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yong-Wei Sun

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  1. Ping Lu
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Correspondence to Li-Wei Wang, Yujie Tang or Jing Xue.

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Lu, P., Geng, J., Zhang, L. et al. THZ1 reveals CDK7-dependent transcriptional addictions in pancreatic cancer. Oncogene 38, 3932–3945 (2019). https://doi.org/10.1038/s41388-019-0701-1

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