Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma.
Junki FukudaShinya KosugeYusuke SatohSho SekiyaRyodai YamamuraTakako OoshioTaiga HirataReo SatoKanako C HatanakaTomoko MitsuhashiToru NakamuraYoshihiro MatsunoYutaka HatanakaSatoshi HiranoMasahiro SonoshitaPublished in: Cancer science (2024)
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.
Keyphrases
- pi k akt
- signaling pathway
- cell cycle arrest
- protein kinase
- induced apoptosis
- drug discovery
- genome wide
- tyrosine kinase
- end stage renal disease
- cell proliferation
- ejection fraction
- chronic kidney disease
- newly diagnosed
- copy number
- climate change
- squamous cell carcinoma
- peritoneal dialysis
- dna methylation
- prognostic factors
- adipose tissue
- weight loss
- single cell
- induced pluripotent stem cells
- transcription factor
- locally advanced
- genome wide analysis