CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Siyuan Zeng - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Bin Lan - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Xiaofan Ren - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Shuman Zhang - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Daniel Schreyer - , University of Glasgow (Author)
  • Markus Eckstein - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Hai Yang - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Nathalie Britzen-Laurent - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Andreas Dahl - , DRESDEN-concept Genome Center (CMCB Core Facility) (Author)
  • Debabrata Mukhopadhyay - , Mayo Clinic Rochester, MN (Author)
  • David Chang - , University of Glasgow, Glasgow Royal Infirmary (Author)
  • Isabella Kutschick - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Susanne Pfeffer - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Peter Bailey - , University of Glasgow (Author)
  • Andrew Biankin - , University of Glasgow, Glasgow Royal Infirmary (Author)
  • Robert Grützmann - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)
  • Christian Pilarsky - , University Hospital at the Friedrich-Alexander University Erlangen-Nürnberg (Author)

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.

Details

Original languageEnglish
Article number241
JournalJournal of Experimental and Clinical Cancer Research
Volume41
Issue number1
Early online date22 Aug 2022
Publication statusPublished - Dec 2022
Peer-reviewedYes

External IDs

PubMed 35945614
Mendeley 8643b0b3-eddb-3c8d-8661-5ee8e8910422

Keywords

DFG Classification of Subject Areas according to Review Boards

Subject groups, research areas, subject areas according to Destatis

ASJC Scopus subject areas

Keywords

  • CDK7, CRISPR-Cas9, FOLFIRINOX, Gemcitabine, Paclitaxel, THZ1, Carcinoma, Pancreatic Ductal/drug therapy, Cyclin-Dependent Kinases/genetics, Xenograft Model Antitumor Assays, Animals, Cell Line, Tumor, Mice, Pancreatic Neoplasms/drug therapy