Glimepiride overcomes acquired resistance to EGFR TKIs in lung cancer via the AMPK/ERK/MMP7 signaling pathway.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-07-12 DOI:10.1016/j.bcp.2025.117162

Hu Zhang, Min Li, Yan Li, Yi Han, Xin Huang, Ling Li

引用次数: 0

Abstract

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) limits their clinical efficacy. Intratumoral heterogeneity and the coexistence of diverse resistance mechanisms make combination therapies focused on single molecules or pathways clinically ineffective. Here, our study demonstrated that glimepiride, a sulfonylurea drug, reversed and delayed acquired resistance to EGFR TKIs in lung cancer. Furthermore, glimepiride not only enhanced apoptosis in resistant cells but also suppressed cancer stemness. Mechanistically, glimepiride exerted these effects through AMPK activation, leading to subsequent suppression of the ERK/MMP7 signaling pathway. Our findings identify glimepiride as a promising therapeutic candidate for combination regimens in lung cancer treatment.

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格列美脲通过AMPK/ERK/MMP7信号通路克服肺癌对EGFR TKIs的获得性耐药。

表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKIs）获得性耐药限制了其临床疗效。肿瘤内的异质性和多种耐药机制的共存使得集中于单分子或途径的联合治疗在临床上无效。本研究表明，磺脲类药物格列美脲可逆转并延缓肺癌患者对EGFR TKIs的获得性耐药。此外，格列美脲不仅能促进耐药细胞的凋亡，还能抑制肿瘤的发生。从机制上讲，格列美脲通过激活AMPK发挥这些作用，导致随后抑制ERK/MMP7信号通路。我们的研究结果确定格列美脲是一种很有前途的肺癌联合治疗方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.