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

  • Tissue Cell. 2026 Jun:100:103365. doi: 10.1016/j.tice.2026.103365.
Xiaozhen Jiang  1 ,  Xia Wen  2 ,  Jiajia Fu  3
Affiliations
  • 1. Department of Pulmonary Medicine, The People's Hospital of PingYang, Wenzhou, Zhejiang 325400, China. Electronic address: [email protected].
  • 2. Department of Pulmonary Medicine, The People's Hospital of PingYang, Wenzhou, Zhejiang 325400, China. Electronic address: [email protected].
  • 3. Department of Pulmonary Medicine, The Second People's Hospital of Yueqing, Wenzhou, Zhejiang 325608, China. Electronic address: [email protected].
PMID: 41687187 DOI: 10.1016/j.tice.2026.103365
Abstract

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.

Keywords
Berberine; Non-small cell lung cancer; Notch1 signaling; Osimertinib resistance.
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