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Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma |
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| Authors: | Junki Fukuda Shinya Kosuge Yusuke Satoh Sho Sekiya Ryodai Yamamura Takako Ooshio Taiga Hirata Reo Sato Kanako C. Hatanaka Tomoko Mitsuhashi Toru Nakamura Yoshihiro Matsuno Yutaka Hatanaka Satoshi Hirano Masahiro Sonoshita |
| Affiliation: | 1. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan Contribution: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing;2. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan Contribution: Formal analysis, Investigation, Writing - review & editing;3. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Contribution: Investigation, Writing - review & editing;4. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan Contribution: Investigation, Writing - review & editing;5. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan Contribution: Formal analysis, Investigation, Writing - review & editing;6. Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan;7. Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan Contribution: Investigation, Writing - review & editing;8. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan Contribution: Investigation, Writing - review & editing;9. Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan Contribution: Investigation, Writing - review & editing;10. Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan Contribution: Investigation, Writing - review & editing;11. Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan Contribution: Investigation, Supervision, Writing - review & editing |
| Abstract: | Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. However, drug discovery for PDAC treatment has proven complicated, leading to stagnant therapeutic outcomes. Here, we identify Glycogen synthase kinase 3 (GSK3) as a therapeutic target through a whole-body genetic screening utilizing a ‘4-hit’ Drosophila model mimicking the PDAC genotype. Reducing the gene dosage of GSK3 in a whole-body manner or knocking down GSK3 specifically in transformed cells suppressed 4-hit fly lethality, similar to Mitogen-activated protein kinase kinase (MEK), the therapeutic target in PDAC we have recently reported. Consistently, a combination of the GSK3 inhibitor CHIR99021 and the MEK inhibitor trametinib suppressed the phosphorylation of Polo-like kinase 1 (PLK1) as well as the growth of orthotopic human PDAC xenografts in mice. Additionally, reducing PLK1 genetically in 4-hit flies rescued their lethality. Our results reveal a therapeutic vulnerability in PDAC that offers a treatment opportunity for patients by inhibiting multiple targets. |
| Keywords: | Drosophila GSK3 MEK pancreatic ductal adenocarcinoma whole-body phenotypic screening |