Frontiers in Pharmacology (Sep 2020)
Screening and Identification of Key Biomarkers in Acquired Lapatinib-Resistant Breast Cancer
Abstract
Lapatinib, targeting the human epidermal growth factor receptor family members HER1 and HER2, has been approved by the US Food and Drug Administration for use in metastatic HER2-positive breast cancer. However, resistance to lapatinib remains a common challenge to HER2-positive metastatic breast cancer. Until now, the molecular mechanisms of acquired resistance to lapatinib (ALR) have remained unclear. With no definite biomarkers currently known, we aimed to screen for key biomarkers in ALR. In this research, we identified 55 differentially expressed genes (DEGs, 20 upregulated, 35 downregulated) through bioinformatic analysis using microarray datasets GSE16179, GSE38376, and GSE51889 from the Gene Expression Omnibus (GEO) database. The related gene function was explored using the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. The functional enrichment of the DEGs was analyzed, including negative regulation of the B cell apoptotic process, DNA replication, solute:proton symporter activity, synthesis, and degradation of ketone bodies, and metal sequestration by antimicrobial proteins. Analysis of seven hub genes revealed their concentration mainly in DNA replication and cell cycle. Survival analysis revealed that MCM10 and SPC24 may be related with poor prognosis in patients with ALR. Meanwhile, the prediction model of lapatinib sensitivity was constructed, and emerging role of the model was further analyzed using several webtools. In conclusion, hub genes are involved in the complex mechanisms underlying ALR in breast cancer and provide favorable support for treatment of ALR in future.
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