PLK1 blockade enhances the anti-tumor effect of MAPK inhibition in pancreatic ductal adenocarcinoma
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.
Authors
- Smiths Lueong (ORCID: https://orcid.org/0000-0002-2776-6706)
- Stephan A. Hahn (ORCID: https://orcid.org/0000-0003-0855-9741)
- Ben Zhao
- Konstantinos Savvatakis
- Laura Godfrey (ORCID: https://orcid.org/0000-0003-2393-9881)
- Rui Fang (ORCID: https://orcid.org/0000-0001-6075-9201)
- Barbara M. Grüner (ORCID: https://orcid.org/0000-0003-0974-4826)
- Hendrik Schürmann
- Kristina Althoff
- Marc Remke (ORCID: https://orcid.org/0000-0002-9404-9993)
- Madeleine Dorsch (ORCID: https://orcid.org/0000-0002-5998-4177)
- Jens Thomas Siveke (ORCID: https://orcid.org/0000-0002-8772-4778)
- Erik Jan Hemmer
- Marija Trajkovic-Arsic
- Jiajin Yang (ORCID: https://orcid.org/0009-0006-8978-1318)
- Gina Lauren Mayer
- Sven T. Liffers
Institutions
- German Cancer Research Center (DE)
- Düsseldorf University Hospital (DE)
- Universitätsklinikum Knappschaftskrankenhaus Bochum (DE)
- Essen University Hospital (DE)
- West German Heart and Vascular Center Essen (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115541
- Citations
- 5
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Natural Science Foundation of Hubei Province
- Deutsche Krebshilfe
- Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie
- Deutschen Konsortium für Translationale Krebsforschung