Screening common signaling pathways associated with drug resistance in non-small cell lung cancer via gene expression profile analysis

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.