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Lycorine Exerts Antitumor Effects on the Osimertinib-Resistant Non-Small Cell Lung Cancer by Inhibiting NOTCH3/HES1

Chen Wang1,2, Chaoyang Zeng1, Aimin Wang1

  • 1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Journal of Biochemical and Molecular Toxicology
|September 15, 2025
PubMed

Insights

Lycorine combats osimertinib resistance in non-small cell lung cancer (NSCLC) by inhibiting the Notch3/Hes1 pathway. This natural compound reduces tumor growth and metastasis, enhancing osimertinib

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) frequently develops resistance to osimertinib, a critical treatment.
  • Lycorine, a natural compound from Amaryllidaceae, exhibits anticancer properties.
  • Understanding mechanisms of osimertinib resistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the efficacy of lycorine against osimertinib-resistant NSCLC cells.
  • To elucidate the underlying molecular mechanisms of lycorine's action.
  • To evaluate lycorine's potential to re-sensitize NSCLC to osimertinib.

Main Methods:

  • Cell viability (CCK8), migration, and wound healing assays were performed on osimertinib-resistant NSCLC cells.
  • In vivo studies utilized xenograft models of osimertinib-resistant NSCLC.
  • Transcriptomic analysis, Western blotting, and gene knockdown were employed to investigate molecular pathways.

Main Results:

  • Lycorine inhibited proliferation and migration of osimertinib-resistant NSCLC cells in vitro and reduced tumor growth in vivo.
  • Lycorine downregulated Notch3 mRNA and protein levels, as well as its downstream effector Hes1.
  • Notch3 and Hes1 were upregulated in resistant cells; their knockdown enhanced osimertinib's efficacy.
  • Lycorine treatment reduced MMP9 and MMP2 protein levels.

Conclusions:

  • Lycorine effectively inhibits proliferation and metastasis in osimertinib-resistant NSCLC.
  • The Notch3/Hes1 signaling pathway is a key mediator of lycorine's anti-cancer effects in this context.
  • Lycorine demonstrates potential as an adjuvant therapy to overcome osimertinib resistance in NSCLC.
Keywords:
Notch3/Hes1drug resistancelycorinenon‐small cell lung cancer (NSCLC)osimertinib

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