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同时靶向 GSK3 和 MEK 作为治疗胰腺导管腺癌的治疗策略。

Concurrent targeting of GSK3 and MEK as a therapeutic strategy to treat pancreatic ductal adenocarcinoma.

机构信息

Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan.

出版信息

Cancer Sci. 2024 Apr;115(4):1333-1345. doi: 10.1111/cas.16100. Epub 2024 Feb 6.

DOI:10.1111/cas.16100
PMID:38320747
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11007052/
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.

摘要

胰腺导管腺癌 (PDAC) 是全球最致命的恶性肿瘤之一。然而，用于 PDAC 治疗的药物发现证明很复杂，导致治疗效果停滞不前。在这里，我们通过利用模拟 PDAC 基因型的“四击”果蝇模型进行全身遗传筛选，将糖原合酶激酶 3 (GSK3) 鉴定为治疗靶点。全身性降低 GSK3 的基因剂量或特异性敲低转化细胞中的 GSK3，可抑制 4 击果蝇的致死性，与我们最近报道的 PDAC 的治疗靶点丝裂原活化蛋白激酶激酶 (MEK) 相似。一致地，GSK3 抑制剂 CHIR99021 和 MEK 抑制剂 trametinib 的组合抑制了 Polo 样激酶 1 (PLK1) 的磷酸化以及在小鼠中荷人 PDAC 异种移植物的生长。此外，在 4 击果蝇中遗传降低 PLK1 可挽救其致死性。我们的结果揭示了 PDAC 中的治疗脆弱性，通过抑制多个靶点为患者提供了治疗机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/dbe48caedf43/CAS-115-1333-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/21acf74451a6/CAS-115-1333-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/fbf34f0d238e/CAS-115-1333-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/3e61ff27dd13/CAS-115-1333-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/c70ae91711d4/CAS-115-1333-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/c9652bf448a8/CAS-115-1333-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/dbe48caedf43/CAS-115-1333-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/21acf74451a6/CAS-115-1333-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/fbf34f0d238e/CAS-115-1333-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/3e61ff27dd13/CAS-115-1333-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/c70ae91711d4/CAS-115-1333-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/c9652bf448a8/CAS-115-1333-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d660/11007052/dbe48caedf43/CAS-115-1333-g007.jpg

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