Overcoming osimertinib resistance in NSCLC: The role of Notch1 pathway inhibition by berberine

BACKGROUND: Resistance acquired during treatment with third-generation EGFR-TKIs, including osimertinib, continues to pose a significant obstacle in the management of advanced non-small cell lung cancer (NSCLC). Dysregulation of the Notch1 signaling pathway plays a critical role in tumor development as well as therapeutic resistance. Berberine (BER), a naturally derived bioactive compound, has been reported to exert diverse antitumor effects across multiple cancer types. METHODS: We investigated Notch1 signaling in osimertinib-resistant NSCLC cells and assessed the effects of combined berberine and osimertinib treatment on epithelial-mesenchymal transition (EMT) and drug sensitivity. RESULTS: Aberrant Notch1 activation promoted EMT and contributed to osimertinib resistance. Berberine inhibited Notch1 signaling, reversed EMT in resistant cells, and restored sensitivity to osimertinib with minimal toxicity. CONCLUSION: Berberine overcomes osimertinib resistance by targeting the Notch1 pathway and reversing EMT, providing a novel strategy to enhance EGFR-TKI efficacy in NSCLC and supporting integration of traditional Chinese medicine with targeted therapies.