Dauricine Overcomes Osimertinib Resistance in Lung Cancer by Inducing Ferroptosis via Stabilizing SAT1

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) for advanced non-small cell lung cancer (NSCLC).
• Resistance to osimertinib is a significant clinical challenge, limiting treatment efficacy.
• Novel strategies are needed to overcome acquired resistance to EGFR-TKIs.

Purpose of the Study:

• To investigate the potential of dauricine, a natural compound, to overcome osimertinib resistance in NSCLC.
• To elucidate the underlying mechanisms of dauricine's action in resistant NSCLC cells.
• To evaluate the therapeutic efficacy of combining dauricine with osimertinib in preclinical models.

Main Methods:

• Utilized osimertinib-resistant NSCLC cell lines and patient-derived organoids.
• Performed mechanistic studies including RNA interference and pharmacological inhibition.
• Assessed tumor growth suppression in vivo using xenograft models.

Main Results:

• Dauricine combined with osimertinib induced ferroptosis in resistant NSCLC cells.
• SAT1 was identified as a critical mediator, with dauricine stabilizing and enhancing its activity.
• The combination therapy significantly suppressed tumor growth in vivo.

Conclusions:

• Dauricine can overcome osimertinib resistance in NSCLC by synergizing with osimertinib to induce ferroptosis.
• SAT1 plays a crucial role in mediating the anti-cancer effects of this combination therapy.
• Combining dauricine with osimertinib represents a potential therapeutic strategy for resistant NSCLC.