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

Zhijie Chen1, Zhuoying Yang1, Yingying Liu1

  • 1Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Toxicology and Applied Pharmacology
|April 5, 2025
PubMed
Abstract

Insights

Jaceosidin, a Traditional Chinese Medicine compound, can overcome osimertinib resistance in non-small cell lung cancer (NSCLC) by interacting with DDB1. Combining jaceosidin with osimertinib enhances targeted therapy efficacy in resistant NSCLC.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Osimertinib, a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI), is crucial for treating advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
  • Acquired resistance to osimertinib significantly limits its long-term clinical efficacy in NSCLC patients.

Purpose of the Study:

  • To establish a TKI-resistant lung cancer model.
  • To identify Traditional Chinese Medicine (TCM) components capable of reversing TKI resistance and resensitizing lung cancer to targeted therapies.
  • To elucidate the molecular mechanisms underlying TKI resistance reversal by TCM compounds.

Main Methods:

  • Development of osimertinib-resistant lung cancer cell lines and organoids via dose escalation.
  • Screening of 302 TCM monomers to identify compounds enhancing osimertinib sensitivity.
  • Utilizing RNA sequencing and limited proteolysis-coupled small molecule mapping to investigate jaceosidin's mechanism of action.
  • In vitro and in vivo validation of the jaceosidin-osimertinib combination in resistant models.

Main Results:

  • Successful establishment of an osimertinib-resistant lung cancer model.
  • Identification of 12 compounds that restore sensitivity to osimertinib, with jaceosidin showing significant efficacy.
  • Jaceosidin, a flavonoid from Eupatorium lindleyanum DC., directly interacts with Damage Specific DNA Binding Protein 1 (DDB1), upregulating its expression.
  • Jaceosidin-induced DDB1 upregulation leads to downregulation of CDK1/Cyclin B1, causing G2/M cell cycle arrest and resensitizing cells to osimertinib.
  • Combined jaceosidin and osimertinib treatment significantly inhibited tumor growth in resistant NSCLC models.

Conclusions:

  • Jaceosidin effectively overcomes osimertinib resistance in NSCLC by modulating DDB1 expression and cell cycle progression.
  • The findings highlight DDB1 as a key player in overcoming EGFR-TKI resistance.
  • Combination therapy with jaceosidin and osimertinib presents a promising strategy to improve treatment outcomes for resistant NSCLC.
Keywords:
Cell cycleEGFR-TKIs resistanceJaceosidinNSCLCOsimertinib

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