TY - JOUR
T1 - Discovery of drug targets and therapeutic agents based on drug repositioning to treat lung adenocarcinoma
AU - Graves, Occam Kelly
AU - Kim, Woonghee
AU - Özcan, Mehmet
AU - Ashraf, Sajda
AU - Turkez, Hasan
AU - Yuan, Meng
AU - Zhang, Cheng
AU - Mardinoglu, Adil
AU - Li, Xiangyu
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/5
Y1 - 2023/5
N2 - Background: Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Although various targeted therapies have been used in the clinical practice, the 5-year overall survival rate of patients is still low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of the LUAD patients. Methods: Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis was used to identify the hub genes driving the tumor development. A profile-based drug repositioning approach was used to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used to measure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression of the proteins. Findings: We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose high expression was associated with poor survival outcomes of patients. Among them, eight genes were identified as hub genes due to their high centrality in the key functional modules in the gene-co-expression network analysis and these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). We performed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drug repositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of each target 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 races and geographic characteristics. We also proved the feasibility of our drug repositioning approach for the development of new drugs for disease treatment.
AB - Background: Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Although various targeted therapies have been used in the clinical practice, the 5-year overall survival rate of patients is still low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of the LUAD patients. Methods: Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis was used to identify the hub genes driving the tumor development. A profile-based drug repositioning approach was used to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used to measure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression of the proteins. Findings: We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose high expression was associated with poor survival outcomes of patients. Among them, eight genes were identified as hub genes due to their high centrality in the key functional modules in the gene-co-expression network analysis and these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). We performed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drug repositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of each target 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 races and geographic characteristics. We also proved the feasibility of our drug repositioning approach for the development of new drugs for disease treatment.
KW - Co-expression network
KW - Drug repositioning
KW - Lung adenocarcinoma
KW - Target identification
UR - http://www.scopus.com/inward/record.url?scp=85149805666&partnerID=8YFLogxK
U2 - 10.1016/j.biopha.2023.114486
DO - 10.1016/j.biopha.2023.114486
M3 - Article
C2 - 36906970
AN - SCOPUS:85149805666
SN - 0753-3322
VL - 161
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 114486
ER -
