CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer

Zeng S, Lan B, Ren X, Zhang S, Schreyer D, Eckstein M, Yang H, Britzen-Laurent N, Dahl A, Mukhopadhyay D, Chang D, Kutschick I, Pfeffer S, Bailey P, Biankin A, Grützmann R, Pilarsky C (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Experimental & Clinical Cancer Research BioMed Central

Book Volume: 41

Article Number: 241

Journal Issue: 1

DOI: 10.1186/s13046-022-02443-w

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Although combined treatment with gemcitabine and albumin-bound paclitaxel has improved the prognosis of PDAC, both intrinsic and acquired chemoresistance remain as severe hurtles towards improved prognosis. Thus, new therapeutic targets and innovative strategies are urgently needed. Methods: In this study, we used the KPC mouse model-derived PDAC cell line TB32047 to perform kinome-wide CRISPR-Cas9 loss-of-function screening. Next-generation sequencing and MAGeCK-VISPR analysis were performed to identify candidate genes. We then conducted cell viability, clonogenic, and apoptosis assays and evaluated the synergistic therapeutic effects of cyclin-dependent kinase 7 (CDK7) depletion or inhibition with gemcitabine (GEM) and paclitaxel (PTX) in a murine orthotopic pancreatic cancer model. For mechanistic studies, we performed genome enrichment analysis (GSEA) and Western blotting to identify and verify the pathways that render PDAC sensitive to GEM/PTX therapy. Results: We identified several cell cycle checkpoint kinases and DNA damage-related kinases as targets for overcoming chemoresistance. Among them, CDK7 ranked highly in both screenings. We demonstrated that both gene knockout and pharmacological inhibition of CDK7 by THZ1 result in cell cycle arrest, apoptosis induction, and DNA damage at least predominantly through the STAT3-MCL1-CHK1 axis. Furthermore, THZ1 synergized with GEM and PTX in vitro and in vivo, resulting in enhanced antitumor effects. Conclusions: Our findings support the application of CRISPR-Cas9 screening in identifying novel therapeutic targets and suggest new strategies for overcoming chemoresistance in pancreatic cancer.

Authors with CRIS profile

Siyuan Zeng Professur für Chirurgische Forschung Bin Lan Professur für Chirurgische Forschung Xiaofan Ren Professur für Chirurgische Forschung Shuman Zhang Professur für Chirurgische Forschung Markus Eckstein Institute of Pathology Hai Yang Department of Surgery Nathalie Britzen-Laurent Medizinische Fakultät Sina Pfeffer Medizinische Fakultät Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Christian Pilarsky Professur für Chirurgische Forschung

Involved external institutions

Mayo Clinic US United States (USA) (US) University of Glasgow GB United Kingdom (GB) Technische Universität Dresden DE Germany (DE)

How to cite

APA:

Zeng, S., Lan, B., Ren, X., Zhang, S., Schreyer, D., Eckstein, M.,... Pilarsky, C. (2022). CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer. Journal of Experimental & Clinical Cancer Research, 41(1). https://doi.org/10.1186/s13046-022-02443-w

MLA:

Zeng, Siyuan, et al. "CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer." Journal of Experimental & Clinical Cancer Research 41.1 (2022).

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