Discovery of drug targets and therapeutic agents based on drug repositioning to treat lung adenocarcinoma

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 t...

Full description

Saved in:

Bibliographic Details
Published in:	Biomedicine & pharmacotherapy Vol. 161; p. 114486
Main Authors:	Graves, Occam Kelly, Kim, Woonghee, Özcan, Mehmet, Ashraf, Sajda, Turkez, Hasan, Yuan, Meng, Zhang, Cheng, Mardinoglu, Adil, Li, Xiangyu
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-05-2023 Elsevier
Subjects:	Adenocarcinoma of Lung - drug therapy Adenocarcinoma of Lung - genetics Adenocarcinoma of Lung - metabolism Co-expression network Drug Repositioning Gene Expression Profiling Humans Lung adenocarcinoma Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Survival Analysis Target identification CDR TPM OS Target identification GO Drug repositioning Lung adenocarcinoma Co-expression network LUAD
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. 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. 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. 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. [Display omitted] •Nine hub genes are essential for the LUAD tumor cell growth and play central roles during the tumor development.•Mitoxantrone and two pre-clinical drugs GCP-60474 and wortmannin are promising for the treatment of LUAD patients.•The drug efficacy has been validated in in vitro cell line model.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007 1950-6007
DOI:	10.1016/j.biopha.2023.114486