FN-1501 Synergistically Enhances Almonertinib Efficacy in EGFR-TKI-ResistantLung Adenocarcinoma through Ferroptosis Induction

INTRODUCTION: The emergence of acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) presents a significant barrier to effective treatment in lung adenocarcinoma. This study investigates the antitumor efficacy of FN-1501 and its potential synergistic interaction with Almonertinib (Alm) to combat this resistance. METHODS: The impact of FN-1501 on lung adenocarcinoma and its synergistic effects with Almonertinib (Alm) were assessed through flow cytometry, Western blot analysis, CCK-8 assays, and clonogenic formation assays. Additionally, transcriptome analysis and network pharmacology were employed to elucidate the functional mechanisms by which FN-1501 may reverse EGFR-TKI acquired resistance. RESULTS: FN-1501 demonstrated the ability to inhibit cell proliferation, induce apoptosis, and arrest the cell cycle. The combination of Alm and FN-1501 restored sensitivity in resistant cell lines. Mechanistic investigations indicated that this combination triggered ferroptosis via the FOXO1-mediated upregulation of NCOA4. In vivo experiments showed that the Alm+FN-1501 combination significantly inhibited tumor growth compared to either treatment alone. DISCUSSION: These results provide compelling evidence that targeting ferroptosis pathways could be a viable approach to overcoming resistance to EGFR-TKIs. The FOXO1/NCOA4 axis emerges as a critical component in this process, enhancing our understanding of the mechanisms underlying resistance. While these findings are promising, further research is needed to evaluate toxicity, pharmacokinetics, and the applicability of this strategy in a broader context of resistance. Identifying predictive biomarkers could help refine patient selection for this treatment approach. CONCLUSION: FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.