CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer

Zeng, S. et al. (2022) CDK7 inhibition augments response to multidrug chemotherapy in pancreatic cancer. Journal of Experimental and Clinical Cancer Research, 41, 241. (doi: 10.1186/s13046-022-02443-w) (PMID:35945614) (PMCID:PMC9364549)

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.

• Item Type: Articles
• Additional Information: Open Access funding enabled and organized by Projekt DEAL. This work was supported by the EU (MSCA-ITN 1705 861196, PRECODE; CP), the Chinese Scholarship Council (CSC Nr. 201906380074 XFR; CSC Nr. 201806880012 SMZ), and the NIH (grant number CA150190; DM).
• Keywords: Research, CRISPR-Cas9, CDK7, Gemcitabine, Paclitaxel, FOLFIRINOX, THZ1
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chang, Professor David and Biankin, Professor Andrew and Bailey, Dr Peter and Schreyer, Mr Daniel
• Authors: 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., and Pilarsky, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Experimental and Clinical Cancer Research
• Publisher: BioMed Central
• ISSN: 1756-9966
• ISSN (Online): 1756-9966
• Copyright Holders: Copyright © The Author(s) 2022
• First Published: First published in Journal of Experimental and Clinical Cancer Research 41: 241
• Publisher Policy: Reproduced under a Creative Commons License