Abstract B066: Repurposed Therapeutic Targets DNA Repair and EGFR Signaling in EGFR-Mutant Lung Cancer

Abstract Lung cancer remains the leading cause of cancer-related mortality globally, with a significant subset driven by mutations in the epidermal growth factor receptor (EGFR). Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are a mainstay of targeted therapy, acquired resistance mutations such as T790M and C797S limit long-term efficacy. The therapeutic potential of repurposed agents against these resistant phenotypes remains underexplored. This study investigated the anticancer effects of a widely used intravenous anesthetic on EGFR-mutant lung cancer cells, including those harboring TKI resistance mutations. We evaluated its cytotoxic effects across a panel of human lung cancer cell lines, including PC9 (EGFR Del19), H1975 (L858R/T790M), and H1975-MS35 (L858R/T790M/C797S). The repurposed agent selectively reduced viability in EGFR-mutant cells, with limited effects on EGFR-wildtype controls. Whole transcriptome RNA sequencing revealed significant downregulation of genes involved in DNA replication, cell cycle progression, homologous recombination (HR), and mismatch repair. Notably, Rad51, a key HR repair protein, was suppressed at both the transcript and protein levels. Functional assays confirmed increased DNA double-strand breaks, G2/M phase arrest, and apoptosis following treatment. Immunoblotting demonstrated concurrent inhibition of EGFR phosphorylation and downstream signaling pathways. Molecular docking studies indicated favorable binding of the agent to mutant EGFR conformations, suggesting a direct molecular interaction. Clinical relevance was supported by The Cancer Genome Atlas (TCGA) data, which showed that high Rad51 expression correlates with poor survival outcomes in lung adenocarcinoma patients. In conclusion, this study demonstrates that a repurposed therapeutic agent exerts selective cytotoxicity against EGFR-mutant and drug-resistant lung cancer cells by dual suppression of EGFR signaling and Rad51-mediated DNA repair. These findings suggest a potential strategy to overcome EGFR-TKI resistance through disruption of homologous recombination, warranting further preclinical investigation. Citation Format: Chi-Yuan Chen, Chieh-Wen Chan, Yu-Xuan Chen. Repurposed Therapeutic Targets DNA Repair and EGFR Signaling in EGFR-Mutant Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B066.