Concurrent Targeting of GSK3 and MEK As a Therapeutic Strategy to Treat Pancreatic Ductal Adenocarcinoma

Overview

Journal Cancer Sci

Specialty Oncology

Date 2024 Feb 6

PMID 38320747

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

Affiliations

Soon will be listed here.

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.

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