Activation of autophagy as a strategy to overcome Osimertinib-resistance in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Mutations in the epidermal growth factor receptor (EGFR) are common in NSCLC, making it a key target for tyrosine kinase inhibitors (TKIs) such as osimertinib. This study examined the relationship between autophagy and osimertinib sensitivity in NSCLC cell lines. In osimertinib-sensitive PC9 cells, osimertinib decreased p62 expression and increased LC3-II conversion, confirming autophagic flux by mCherry-EGFP-LC3B transfection. Conversely, A549 cells, which are insensitive to osimertinib-induced cell death, did not show autophagy induction. Importantly, rapamycin-induced autophagy sensitized A549 cells to osimertinib. We also established an osimertinib-resistant cell line, PC9/OR, to explore the role of autophagy in acquired resistance. Osimertinib failed to induce autophagy in PC9/OR cells, similar to A549 cells. However, rapamycin-induced autophagy significantly reduced colony formation in PC9/OR cells. In a xenograft mouse model, combined treatment with rapamycin and osimertinib reduced tumor size more effectively than either treatment alone. These findings suggest that modulating autophagy can overcome acquired resistance to EGFR-TKIs, potentially enhancing osimertinib efficacy and allowing lower drug doses to minimize side effects. Overall, this study highlights the dual role of autophagy in NSCLC and its importance in therapeutic response, providing new insights into treatment strategies for patients with osimertinib-resistant NSCLC.