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Meta-Analysis
. 2023 Dec 31;24(1):2253586.
doi: 10.1080/15384047.2023.2253586.

Drug repurposing based on differentially expressed genes suggests drug combinations with possible synergistic effects in treatment of lung adenocarcinoma

Liora Yesharim  1 , Shahram Teimourian  1
Affiliations
Meta-Analysis

Drug repurposing based on differentially expressed genes suggests drug combinations with possible synergistic effects in treatment of lung adenocarcinoma

Liora Yesharim et al. Cancer Biol Ther. .

Abstract

Lung adenocarcinoma is one of the leading causes of cancer-related mortality globally. Various treatment approaches and drugs had little influence on overall survival; thus, new drugs and treatment strategies are needed. Drug repositioning (repurposing) seems a favorable approach considering that developing new drugs needs much more time and costs. We performed a meta-analysis on 6 microarray datasets to obtain the main genes with significantly altered expression in lung adenocarcinoma. Following that, we found major gene clusters and hub genes. We assessed their enrichment in biological pathways to get insight into the underlying biological process involved in lung adenocarcinoma pathogenesis. The L1000 database was explored for drug perturbations that might reverse the expression of differentially expressed genes in lung adenocarcinoma. We evaluated the potential drug combinations that interact the most with hub genes and hence have the most potential to reverse the disease process. A total of 2148 differentially expressed genes were identified. Six main gene clusters and 27 significant hub genes mainly involved in cell cycle regulation have been identified. By assessing the interaction between 3 drugs and hub genes and information gained from previous clinical investigations, we suggested the three possible repurposed drug combinations, Vorinostat - Dorsomorphin, PP-110 - Dorsomorphin, and Puromycin - Vorinostat with a high chance of success in clinical trials.

Keywords: Lung adenocarcinoma; differentially expressed genes; drug repositioning; drug repurposing; hub genes; meta-analysis.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
The density and PCA plot of the six microarray datasets, (a) before and (b) after batch effect removal.
Figure 2.
Figure 2.
Q-Q plot drawn after submitting the six datasets to (www.networkanalyst.ca). The red line indicates the chi-squared distribution. This Q-Q plot shows that the distribution of the datasets used for meta-analysis is different.
Figure 3.
Figure 3.
(a) The six main gene clusters and the pathways they are enriched in. (b) 30 hub genes in the PPI network. The color spectrum from red (higher score) to yellow (lower score) indicates the MCC score for each node.
Figure 4.
Figure 4.
Validation of the expression of the 30 hub genes based on TCGA and GTEx data in GEPIA (http://gepia.cancer-pku.cn). *P<.01. The y-axis unit represents Log2(TPM +1). Transcripts per Million (TPM).
Figure 5.
Figure 5.
Overall survival and analyses of the 27 validated hub genes were performed using GEPIA.
Figure 6.
Figure 6.
The interactions between the top three drug combinations with the DEGs. Hub genes showed with V shapes. combinedES= combined effect size.
See this image and copyright information in PMC

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