2024 Asia Conference on Lung Cancer (ACLC) - Poster & ePosters-PP02.47

PP02.47 - Wenmei Su

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The study investigates the combination of osimertinib and chidamide as a potential therapeutic strategy to overcome acquired resistance to osimertinib in non-small cell lung cancer (NSCLC) with the EGFR T790M mutation. Osimertinib alone has proven effective in treating NSCLC, but resistance often develops, necessitating new treatment approaches.<br /><br />Researchers conducted experiments using various cell lines and mouse models to explore the effects of osimertinib and chidamide, both separately and in combination, on the proliferation, migration, and survival of drug-resistant and sensitive NSCLC cells. The findings indicate that the combination therapy effectively reverses acquired resistance to osimertinib.<br /><br />A significant discovery was the role of SRSF3 in mediating drug resistance. SRSF3 upregulates the acetylation of YBX1, which enhances EGFR phosphorylation and subsequently activates the ERK signaling pathway. This activation promotes autophagy, contributing to tumor progression and drug resistance. Knocking down SRSF3 using specific siRNAs reduced YBX1 acetylation and sensitized resistant cells to osimertinib, diminishing their viability and migration capability.<br /><br />The study reveals that the addition of chidamide effectively inhibits SRSF3 expression, reducing YBX1 acetylation, and thus lowering p-EGFR levels and autophagy activity. This mechanism suggests that chidamide, when combined with osimertinib, can effectively counteract resistance, halt tumor progression, and improve patient outcomes.<br /><br />Furthermore, next-generation sequencing (NGS) analysis showed differential gene expression linked to resistance and identified up- and downregulated genes involved. Higher SRSF3 expression was correlated with poorer lung adenocarcinoma patient survival, indicating its potential as a prognostic marker. Overall, this research highlights a promising combination strategy to overcome osimertinib resistance in NSCLC treatment.

Keywords

osimertinib

chidamide

NSCLC

EGFR T790M mutation

drug resistance

SRSF3

YBX1 acetylation

ERK signaling pathway

autophagy

next-generation sequencing