Abstract
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) widely used to treat advanced nonsmall cell lung cancer (NSCLC) with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness. In this study, we used osimertinib-resistant lung cancer cell lines and lung cancer patient-derived organoids to demonstrate the potential of dauricine, a bioactive compound derived from menispermum dauricum, to overcome osimertinib resistance in lung cancer cells. Mechanistic studies reveal that dauricine, when combined with osimertinib, efficiently induces ferroptosis in resistant lung cancer cells. Notably, RNA interference and pharmacological inhibition assays identify SAT1, a key enzyme involved in polyamine metabolism and oxidative stress regulation, as a critical mediator of the synergistic effects observed with the dauricine-osimertinib combination therapy. Furthermore, we show that dauricine can directly interact with and stabilize SAT1 to enhance its activity. In vivo, when administered with osimertinib, dauricine significantly suppresses tumor growth in osimertinib-resistant lung cancer models. These findings provide novel insights into the role of SAT1 in overcoming osimertinib resistance and suggest that combining dauricine with osimertinib could be a promising therapeutic strategy to improve the efficacy of EGFR-TKI therapy in resistant NSCLC.