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Updated: Jan 31, 2026

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Magnolol suppresses TKI-resistant EGFR-mutant lung cancer by inhibiting EGFR and AXL-cMyc

Chin-Chuan Chen1, Tong-Hong Wang2, Yann-Lii Leu1

  • 1Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan; BioBank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

European Journal of Pharmacology
|January 29, 2026
PubMed

Insights

Magnolol, a natural compound, combats drug resistance in EGFR-mutant lung cancer by targeting multiple pathways. It inhibits epidermal growth factor receptor (EGFR) and the AXL-cMyc axis, enhancing sensitivity to therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), like osimertinib, is a significant hurdle in treating EGFR-mutant lung cancer.
  • Tertiary mutations, such as C797S, contribute to resistance and necessitate novel therapeutic strategies.

Purpose of the Study:

  • To investigate the pharmacological activity of magnolol, a natural biphenolic compound, against EGFR-mutant lung cancer, including osimertinib-resistant models.
  • To elucidate the molecular mechanisms underlying magnolol's effects and its potential as an adjuvant therapy.

Main Methods:

  • Evaluation of magnolol's effects on proliferation and apoptosis in sensitive and resistant lung cancer cell lines.
  • Molecular docking and cellular thermal shift assays to assess EGFR engagement.
  • Analysis of signaling pathways including AXL-cMyc and DNA repair mechanisms (Rad51).
  • Assessment of combination therapy with brigatinib in xenograft models and patient data analysis.

Main Results:

  • Magnolol inhibited proliferation and induced apoptosis in EGFR-mutant lung cancer cells, including those resistant to osimertinib.
  • Magnolol directly engaged mutant EGFR, reducing its phosphorylation, and suppressed the AXL-cMyc signaling axis.
  • Magnolol impaired homologous recombination repair by downregulating Rad51, leading to DNA damage accumulation.
  • Combination therapy with brigatinib demonstrated enhanced antitumor activity and improved inhibition of key signaling molecules.

Conclusions:

  • Magnolol exhibits multitargeted activity against EGFR-mutant lung cancer by inhibiting mutant EGFR, suppressing the AXL-cMyc axis, and disrupting DNA repair.
  • Magnolol shows promise as an adjuvant strategy to overcome acquired resistance to EGFR-TKIs in lung cancer.
  • High co-expression of AXL, cMyc, and Rad51 correlates with worse patient survival, highlighting the clinical relevance of this axis.
Keywords:
AXLDNA damage repairEGFRLung cancerMagnolol

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