The combination of USP24-i-101-Astemizole sensitizes the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer

In this study, we utilized the yeast two-hybrid system to screen for proteins interacting with USP24. Out of 250 such proteins, functional enrichment analysis using MetaCore™ indicated that 33 of them were involved in lung cancer progression. We then investigated gene expression and survival rates of these 33 proteins in lung cancer patients and cell lines through TCGA databases, Kaplan-Meier Plotter databases, and RNA-seq profile from A549/A549-T24 cells. By employing the patients' survival rate and gene expression profile of these 33 USP24-interacting proteins as gene signatures, we identified 10 potential drugs for inhibiting lung cancer progression or drug resistance via drug repurposing strategy using the Connectivity Map (CMap) database. Of these 10 drugs, six showed similar indicators in Clinical Trials, while the other four candidates (15-delta prostaglandin J2, Astemizole, Trifluoperazine, and 1,4-chrysenequinone) were chosen to evaluate their effect on re-sensitizing cytotoxicity of Taxol and Gefitinib in drug-resistant cancer cells. Experiments demonstrated that treatment with USP24-i-101 and Astemizole alone significantly inhibited drug resistance and re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer cells. Notably, combination therapy with USP24-i-101and Astemizole re-sensitized the cytotoxicity of Taxol and Gefitinib in drug-resistant lung cancer, which could benefit in inhibiting drug resistance during cancer therapy.