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.
Highlights
Based on molecular markers, breast cancer is divided into four subgroups: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 (HER2)-enriched (Perou et al, 2000)
Lapatinib has been approved for treating HER2positive metastatic breast cancer after trastuzumab failure, acquired resistance to lapatinib (ALR) remains a major clinical challenge
In-depth study of the mechanism of ALR and discovery of biomarkers with high sensitivity and specificity are of great value to improve the prognosis of patients with HER2positive breast cancer
Summary
Breast cancer is divided into four subgroups: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 (HER2)-enriched (Perou et al, 2000). Receptor tyrosine-protein kinase HER2, known as erbB-2, is included in the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (Oh and Bang, 2020). A reversible tyrosine kinase inhibitor with specificity for both EGFR and HER2, is approved for treating HER2-positive metastatic breast cancer after disease progression with trastuzumab therapy (Gradishar, 2013; Moasser and Krop, 2015). D’Amato et al have pointed out multiple mechanisms of ALR in breast cancers, including activation of compensatory pathways, mutation of the HER2 kinase domain, and gene amplification (D’Amato et al, 2015). There are currently no definite biomarkers to predict patients’ responses to lapatinib
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call