Jaceosidin overcomes osimertinib resistance in lung cancer by inducing G2/M cycle arrest through targeting DDB1

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-04-03 DOI:10.1016/j.taap.2025.117327

Zhijie Chen , Zhuoying Yang , Yingying Liu, Zehao Zhou, Biying Men, Liang Yun, Jianjun Jiang, Haotian Ge, Meijuan Dian, Yujing He, Ruihao Zhang, Kaican Cai, Xuguang Rao, Shuan Rao

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引用次数: 0

Abstract

Background

Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used to treat advanced non-small cell lung cancer with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness.

Purpose

This study aimed to establish a lung cancer TKI-resistant model and identify Traditional Chinese Medicine (TCM) components that could reverse TKI resistance, enhancing lung cancer sensitivity to targeted therapies, while exploring the underlying molecular mechanisms.

Materials and methods

Osimertinib-resistant cell lines and organoids were developed using a dose-escalation approach. A screen of 302 traditional Chinese medicine monomers revealed compounds that increased sensitivity to osimertinib. RNA sequencing and limited proteolysis coupled with small molecule mapping were employed to investigate the molecular mechanisms by which jaceosidin reverses resistance. The efficacy of the jaceosidin and osimertinib combination was confirmed in cell lines, organoids, and a mouse model.

Results

The osimertinib-resistant lung cancer model was successfully established, and 12 compounds were identified that enhanced the sensitivity of resistant cells to osimertinib. Among these, Jaceosidin, a flavonoid compound derived from Eupatorium lindleyanum DC., was confirmed to notably increase osimertinib sensitivity. Mechanistic studies, including limited proteolysis and RNA interference analysis, demonstrated that Jaceosidin directly interacts with Damage Specific DNA Binding Protein 1 (DDB1), promoting its protein expression and downregulating CDK1/Cyclin B1 levels. This interaction induced G2/M cell cycle arrest, thereby sensitizing lung cancer cells to osimertinib. Furthermore, both in vitro and in vivo experiments confirmed that the combination of Jaceosidin and osimertinib significantly inhibited tumor growth in osimertinib-resistant models.

Conclusion

These findings offer new insights into the role of DDB1 in overcoming osimertinib resistance and suggest that combining jaceosidin with osimertinib may serve as a promising therapeutic strategy to enhance the efficacy of EGFR-TKIs treatment in resistant Non-small Cell Lung Cancer (NSCLC).

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.