2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.17 Exploring Autophagy Flux-Related Molecules to Overcome in Acquired Resistance to EGFR TKIs in NSCLC Patients Harboring EGFR Mutations

P3.03I.17 Exploring Autophagy Flux-Related Molecules to Overcome in Acquired Resistance to EGFR TKIs in NSCLC Patients Harboring EGFR Mutations

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The document presents a study conducted to explore autophagy flux-related molecules to overcome acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutations. The research aimed to understand the role of autophagy in drug resistance by identifying signaling molecules associated with the process in mutant EGFR NSCLC. Using cell lines resistant to osimertinib and erlotinib, methods included electron microscopy, qRT-PCR, western blotting, and siRNA knockdown assays to analyze genes driving autophagy flux activity.<br /><br />Results indicated that specific mRNA expressions of autophagy-related genes, such as BECLIN1, PINK1, GABARAPL1, NBR1, and ULK1, were significantly higher in resistant cell lines compared to parental ones. The study found that inhibition of ULK1 and GABARAPL1 using siRNAs reduced cell proliferation and affected protein expressions involved in autophagy. Notably, osimertinib did not significantly alter cell viability post-treatment, whereas hydroxychloroquine, an autophagy inhibitor, markedly decreased cell viability in resistant cells, highlighting the potential of autophagy inhibition in overcoming drug resistance.<br /><br />Furthermore, increased p-Beclin1 protein expression was observed in tumor tissues after treatment failures, reinforcing the connection between autophagy and drug resistance. The findings suggest that autophagy-related genes ULK1 and GABARAPL1 are closely linked with osimertinib-induced resistance, opening avenues for further RNA profiling and functional studies to target these molecules for overcoming EGFR TKI resistance. The research was supported by the National Research Foundation of Korea, indicating the significance of this study in addressing drug resistance in NSCLC therapy.

Asset Subtitle

Jeong-Oh Kim

Meta Tag

Speaker Jeong-Oh Kim

Topic Tumor Biology – Translational Biology

Keywords

autophagy

EGFR mutations

non-small cell lung cancer

tyrosine kinase inhibitors

drug resistance

ULK1

GABARAPL1

osimertinib

hydroxychloroquine

siRNA knockdown