A Dual Adjunct Modulation To Co-Sensitize Osmertinib-Refractory Small-Cell Transformed EGFR-Mutant Non-Small Cell Lung Cancer To Ferroptosis: Leveraging The Potentially Synergistic Effects of Dauricine and Curcumin.

Introduction

Osmertinib, a third-generation EGFR-TKI inhibitor, is known as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, acquired resistance occurs with histological small-cell transformation in around 15% of cases. This necessitates the development of adjunctive strategies targeting a therapeutic vulnerability found in such phenotypic neuroendocrine progression; ferroptosis susceptibility. Ferroptosis is marked by increased intracellular free ferrous ion concentration, autocatalytic lipid peroxidation, and subsequent cell death. In such cases, the transformed cells exhibit dysregulated iron metabolism, creating a tumor microenvironment (TME) primed for Dauricine and Curcumin in regulating ferroptosis effectors – showing promise as a polytherapy regimen.

Methods

Articles were searched via PubMed and SCOPUS (2015-2025). Search terms included the following: “SCLC transformation”, “EGFR NSCLC”, “osmertinib resistance”. Final selection was made considering mechanistic implications to propose an integrative thematic model.

Results

Dauricine promotes polyamine catabolism and accumulation of ROS via SAT1 stabilization. Curcumin, a pro-autophagic agent downregulates circFOXP1, liberating miR-520a-5p, which decreases SLC7A11 activity. The net synergistic result is an increase in malondialdehyde, alongside impairment of GPX4-mediated antioxidant defense driven by enhanced ROS and glutathione depletion, overburdening the intrinsic antioxidant buffer capacity via positive feedback. Consequently, lipid peroxidation events propagate within the TME – a crucial hallmark of ferroptosis.

Conclusion

In conclusion, this novel strategy demonstrates therapeutic potential by targeting ferroptosis via metabolic and epigenetic nodes - with both compounds demonstrating overlapping modulatory activity, giving rise to possible synergism. This warrants further experimental validation of combined PK-PD parameters for this resistance phenotype using lung cancer xenografts.