A B S T R A C T
Background: Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Althoughvarious targeted therapies have been used in the clinical practice, the 5-year overall survival rate of patients isstill low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of theLUAD patients.Methods: Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis wasused to identify the hub genes driving the tumor development. A profile-based drug repositioning approach wasused to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used tomeasure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression ofthe proteins.Findings: We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose highexpression was associated with poor survival outcomes of patients. Among them, eight genes were identified ashub genes due to their high centrality in the key functional modules in the gene-co-expression network analysisand these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). Weperformed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drugrepositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of eachtarget gene and validated the drug efficacy by performing in vitro experiments.Interpretation: We found the consensus targetable genes for the treatment of LUAD patients with different racesand geographic characteristics. We also proved the feasibility of our drug repositioning approach for thedevelopment of new drugs for disease treatment.
