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

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, remains a major therapeutic challenge in EGFR-mutant lung cancer. In this study, we evaluated the pharmacological activity of magnolol, a natural biphenolic compound, in EGFR-mutant lung cancer models, including osimertinib-resistant cells harboring tertiary mutations such as C797S. Magnolol inhibited proliferation and induced apoptosis in both sensitive and resistant cell lines. Molecular docking and cellular thermal shift assays suggested cellular engagement of magnolol with the ATP-binding pocket of mutant EGFR, accompanied by reduced EGFR phosphorylation. In addition, magnolol suppressed the AXL receptor tyrosine kinase (AXL)-cMyc signaling axis and impaired homologous recombination repair by downregulating Rad51, leading to accumulation of DNA damage. These effects were enhanced when combined with brigatinib, a clinically approved multi-kinase inhibitor with activity against mutant EGFR. In xenograft models, magnolol enhanced the antitumor activity of brigatinib through increased inhibition of EGFR, AXL, cMyc, Rad51, and Ki-67. Furthermore, Kaplan-Meier analysis demonstrated that patients with high co-expression of AXL, cMyc, and Rad51 had significantly worse survival, supporting the clinical relevance of this axis. Collectively, these findings suggest that magnolol exerts multitargeted effects involving inhibition of mutant EGFR, suppression of the AXL-cMyc signaling axis, and disruption of DNA repair, thereby sensitizing resistant tumors to EGFR-TKIs. Magnolol may represent a promising adjuvant strategy for overcoming acquired resistance in EGFR-mutant lung cancer.