Screening common signaling pathways associated with drug resistance in non-small cell lung cancer via gene expression
Ting Sun1,2, Qitai Zhao1,3, Chaoqi Zhang1,3
1Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Lung cancer is the leading cause of cancer-related deaths worldwide. Although several therapeutic strategies have been employed to curb lung cancer, the survival rate is still poor owing to the development of drug resistance. The mechanisms underlying drug resistance development are incompletely understood. Here, we aimed to identify the common signaling pathways involved in drug resistance in non-small cell lung cancer (NSCLC). Three published transcriptome microarray data were downloaded from the Gene Expression Omnibus (GEO) database comprising different drug-resistant cell lines and their parental cell lines. Differentially expressed genes (DEGs) were identified and used to perform Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. An overlapping analysis was performed for KEGG pathways enriched from all the three datasets to identify the common signaling pathways. As a result, we found that metabolic pathways, ubiquitin-mediated proteolysis, and mitogen-activated protein kinase (MAPK) signaling were the most aberrantly expressed signaling pathways. The knockdown of nicotinamide phosphoribosyltransferase (NAMPT), the gene involved in metabolic pathways and known to be upregulated in drug-resistant tumor cells, was shown to increase the apoptosis of cisplatin-resistant A549 cells following cisplatin treatment. Thus, our results provide an in-depth analysis of the signaling pathways that are commonly altered in drug-resistant NSCLC cell lines and highlight the potential strategy that facilitates the development of interventions to interfere with upregulated signaling pathways as well as to boost downregulated signaling pathways in drug-resistant tumors for the elimination of multiple resistance of NSCLC.
Insights
Drug resistance in non-small cell lung cancer (NSCLC) is a major challenge. This study identified common signaling pathways, including metabolic and MAPK pathways, involved in NSCLC drug resistance, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Poor survival rates in lung cancer are often due to acquired drug resistance.
- Mechanisms of drug resistance in non-small cell lung cancer (NSCLC) require further elucidation.
Purpose of the Study:
- To identify common signaling pathways implicated in drug resistance in non-small cell lung cancer (NSCLC).
- To analyze differentially expressed genes and enriched pathways in drug-resistant NSCLC cell lines.
Main Methods:
- Downloaded and analyzed three Gene Expression Omnibus (GEO) transcriptome microarray datasets.
- Performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses on differentially expressed genes (DEGs).
- Conducted overlapping analysis of KEGG pathways to identify commonly altered pathways.
Main Results:
- Metabolic pathways, ubiquitin-mediated proteolysis, and mitogen-activated protein kinase (MAPK) signaling were identified as commonly dysregulated pathways.
- Knockdown of NAMPT, a gene in metabolic pathways, increased apoptosis in cisplatin-resistant A549 cells.
- Identified key signaling pathways associated with multi-drug resistance in NSCLC.
Conclusions:
- Common signaling pathways, including metabolic and MAPK pathways, are crucial in NSCLC drug resistance.
- Targeting upregulated pathways like NAMPT presents a potential therapeutic strategy for overcoming drug resistance.
- Findings provide insights for developing novel interventions against drug-resistant NSCLC.
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