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通过AMPK/mTOR途径靶向CDK4/6和MEK对胃癌自噬的协同诱导作用。

Synergistic induction of autophagy in gastric cancer by targeting CDK4/6 and MEK through AMPK/mTOR pathway.

作者信息

Zhou Hong, Li Guiling, Kan Liuyue, Yang Mingyu, Liu Yu, Miu Xiaye, Shi Lei, Yang Zhanjun, Zheng Xucai, Chen Hui, Ren Chuanli

机构信息

Department of Laboratory Medicine, Clinical College of Yangzhou University and Northern Jiangsu People's Hospital, Yangzhou, Jiangsu, 225001, China.

Department of Gastrointestinal Surgery, Clinical College of Yangzhou University, Yangzhou, Jiangsu, 225001, China.

出版信息

Heliyon. 2024 Apr 29;10(9):e30475. doi: 10.1016/j.heliyon.2024.e30475. eCollection 2024 May 15.

DOI:10.1016/j.heliyon.2024.e30475
PMID:38726124
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11079098/
Abstract

is a commonly mutated oncogene in human gastric cancer and is often associated with drug resistance and poor prognosis. Co-clinical trial of combined MEK-CDK4/6 inhibition in AS mutated cancers demonstrated therapeutic efficacy in patient-derived xenografts and safety in patients. Here, present research focuses on targeting CDK4/6 and MEK synergistically block the proliferation of -mutated gastric cancer cells in vitro and in vivo and induced autophagy through the AMPK/mTOR pathway. Furthermore, autophagy inhibitor combined with targeting CDK4/6 and MEK therapy had significant antitumor effects on mutant gastric cancer cells. Clinical trials are needed to determine the mechanism behind this finding and its clinical utility. In conclusion, our results demonstrate autophagy inhibitor combined targeting MEK and CDK4/6 that concurrently block multiple metabolic processes may be an effective therapeutic approach for gastric cancer.

摘要

是人类胃癌中常见的突变癌基因，常与耐药性和不良预后相关。在AS突变癌症中联合MEK - CDK4/6抑制的联合临床试验证明了在患者来源的异种移植模型中的治疗效果以及对患者的安全性。在此，目前的研究聚焦于协同靶向CDK4/6和MEK以在体外和体内阻断AS突变的胃癌细胞增殖，并通过AMPK/mTOR途径诱导自噬。此外，自噬抑制剂与靶向CDK4/6和MEK治疗联合对AS突变的胃癌细胞具有显著的抗肿瘤作用。需要进行临床试验以确定这一发现背后的机制及其临床实用性。总之，我们的结果表明，联合靶向MEK和CDK4/6并同时阻断多个代谢过程的自噬抑制剂可能是胃癌的一种有效治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/5858cb81cbf9/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/724828fb4146/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/87a98074abd1/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/a1eb3ca38362/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/9e957323d2d1/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/5858cb81cbf9/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/724828fb4146/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/87a98074abd1/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/a1eb3ca38362/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/9e957323d2d1/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad6f/11079098/5858cb81cbf9/gr5.jpg

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Cancer Res. 2023 Jan 4;83(1):141-157. doi: 10.1158/0008-5472.CAN-22-0391.
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Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6.双重抑制 MEK 和 CDK4/6 靶向治疗 RAS 突变型结直肠癌。
Cancer Res. 2022 Sep 16;82(18):3335-3344. doi: 10.1158/0008-5472.CAN-22-0198.
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Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.
选择性多激酶抑制通过重塑肿瘤微环境使间充质胰腺癌细胞对免疫检查点阻断敏感。
Nat Cancer. 2022 Mar;3(3):318-336. doi: 10.1038/s43018-021-00326-1. Epub 2022 Jan 31.
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Acquired Resistance to KRAS Inhibition in Cancer.癌症中对 KRAS 抑制的获得性耐药。
N Engl J Med. 2021 Jun 24;384(25):2382-2393. doi: 10.1056/NEJMoa2105281.
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KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments.KRAS 继发突变导致对 KRAS G12C 抑制剂（索托拉西布和阿达格拉西布）获得性耐药及克服策略：体外实验的见解。
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