Cell Reports (Apr 2025)
PLK1 blockade enhances the anti-tumor effect of MAPK inhibition in pancreatic ductal adenocarcinoma
- Ben Zhao,
- Rui Fang,
- Hendrik Schürmann,
- Erik Jan Hemmer,
- Gina Lauren Mayer,
- Marija Trajkovic-Arsic,
- Kristina Althoff,
- Jiajin Yang,
- Laura Godfrey,
- Sven T. Liffers,
- Konstantinos Savvatakis,
- Madeleine Dorsch,
- Barbara M. Grüner,
- Stephan Hahn,
- Marc Remke,
- Smiths S. Lueong,
- Jens T. Siveke
Affiliations
- Ben Zhao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Rui Fang
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Hendrik Schürmann
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany
- Erik Jan Hemmer
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Gina Lauren Mayer
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Marija Trajkovic-Arsic
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Kristina Althoff
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Jiajin Yang
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Laura Godfrey
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Sven T. Liffers
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Konstantinos Savvatakis
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany
- Madeleine Dorsch
- German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany
- Barbara M. Grüner
- German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147 Essen, Germany
- Stephan Hahn
- Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany; Department of Internal Medicine, Ruhr University Bochum, Knappschaftskrankenhaus, 44780 Bochum, Germany
- Marc Remke
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada; Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 40225 Düsseldorf, Germany
- Smiths S. Lueong
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany; Corresponding author
- Jens T. Siveke
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany; German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147 Essen, Germany; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2025.115541
- Journal volume & issue
-
Vol. 44,
no. 4
p. 115541
Abstract
Summary: Despite constitutive Ras/Raf/MAPK pathway activation in most pancreatic ductal adenocarcinomas (PDACs), treatment approaches targeting this pathway have primarily been unsuccessful. We conduct a drug library screen on an MEK inhibitor (MEKi)-resistant PDAC model and perform complementary pathway analysis to identify cellular resistance phenotypes. We use syngeneic models to investigate the molecular determinants of identified drug synergism. Our study reveals an enrichment for the hallmarks of G2/M checkpoints in MEKi-resistant phenotypes from all investigated models. We find overexpression of Polo-like kinase 1 (PLK1) and other G2/M checkpoint-related proteins in MEKi-resistant cells. We identify synergistic activity between MEK and PLK1 inhibition both in vitro and in vivo and mechanistically show that dual inhibition of the PLK1 and MEK pathways activates the JNK/c-JUN pathway. This causes the accumulation of DNA damage, ultimately leading to apoptotic cell death. Dual PLK1/MEK inhibition emerges as a promising targeted approach in PDAC.
Keywords
