Aumolertinib combined with targeting in the treatment of non-small cell lung cancer.

[BACKGROUND] Lung cancer is a leading cause of cancer deaths. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have improved outcomes for -mutant non-small cell lung cancer (NSCLC), but acquired resistance remains a major challenge. Third-generation EGFR-TKIs like aumolertinib show efficacy, yet their molecular mechanisms and sensitivity optimization need further exploration. The aim of this study is to enhance the efficacy of aumolertinib in the treatment of NSCLC.

[METHODS] experiments using PC-9 cells included Cell Counting Kit-8 (CCK-8) assays (cell viability), wound healing assays (migration), flow cytometry (apoptosis/cell cycle), RNA sequencing (RNA-seq), public transcriptome datasets (GSE193258, GSE178975) were analyzed to compare ETS variant transcription factor 4 () expression across EGFR-TKIs (aumolertinib, osimertinib, and gefitinib). Small interfering RNA (siRNA) mediated knockdown of was verified through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. validation employed BALB/C nude mouse xenograft models treated with aumolertinib, siRNA (si), or their combination.

[RESULTS] Aumolertinib time- and dose-dependently inhibited PC-9 viability, inducing G2/M arrest, apoptosis, and migration suppression. RNA-seq and cross-dataset analysis identified as a conserved differentially expressed gene (DEG) across EGFR-TKI generations. knockdown enhanced aumolertinib-induced apoptosis/G2/M arrest and synergistically suppressed tumor growth .

[CONCLUSIONS] These findings revealed that enhanced the therapeutic efficacy of aumolertinib and , indicating that is a potential therapeutic co-target, serving as a treatment strategy to prevent the acquired resistance induced by aumolertinib.