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

Biomed Pharmacother. 2023 Mar 10;161:114486. doi: 10.1016/j.biopha.2023.114486.

Occam Kelly Graves ¹, Woonghee Kim ², Mehmet Özcan ³, Sajda Ashraf ⁴, Hasan Turkez ⁵, Meng Yuan ⁶, Cheng Zhang ⁷, Adil Mardinoglu ⁸, Xiangyu Li ⁹

Affiliations

1 Harvey Mudd College, Claremont, CA 91711, USA. Electronic address: occamkg@gmail.com.
2 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden. Electronic address: woonghee.kim@scilifelab.se.
3 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden. Electronic address: mehmet.ozcan@scilifelab.se.
4 Trustlife Labs, Drug Research & Development Center, 34774 Istanbul, Turkey. Electronic address: Sajda.ashraf@trustlifelabs.com.
5 Trustlife Labs, Drug Research & Development Center, 34774 Istanbul, Turkey. Electronic address: hturkez@atauni.edu.tr.
6 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden. Electronic address: meng.yuan@scilifelab.se.
7 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden. Electronic address: cheng.zhang@scilifelab.se.
8 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK. Electronic address: adilm@scilifelab.se.
9 Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden; Bash Biotech Inc, 600 West Broadway, Suite 700, San Diego, CA 92101, USA; Guangzhou Laboratory, Guangzhou 510005, China. Electronic address: xiangyu.li@scilifelab.se.

PMID: 36906970 DOI: 10.1016/j.biopha.2023.114486

Abstract

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.

Keywords

Co-expression network; Drug repositioning; Lung adenocarcinoma; Target identification.

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HY-11009

CGP60474

99.23%, CDK/PKC Inhibitor

CDK; PKC

Cancer

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