Bioinformatics-based screening of key genes for transformation of tyrosine kinase inhibitor-resistant lung adenocarcinoma to small cell lung cancer.

PURPOSE: Lung adenocarcinoma (LUAD) is a common type of lung cancer. Cancer in a small number of patients with EGFR mutations will transform from LUAD to small cell lung cancer (SCLC) during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapiesr. The purpose of the present study was to identify the core genes related to the transformation of LUAD into SCLC and to explore the associated molecular mechanisms.

METHODS: GSE29016, GSE1037, GSE6044 and GSE40275 mRNA microarray datasets from Gene Expression Omnibus (GEO) were analyzed to obtain differentially expressed genes (DEGs) between LUAD and SCLC tissues, and the results were used for network analysis of protein-protein interactions (PPIs). After identifying the hub gene by STRING and Cytoscape platform, we explored the relationship between hub genes and the occurrence and development of SCLC. Finally, the obtained hub genes were validated in treated LUAD cells.

RESULTS: A total of 41 DEGs were obtained, four hub genes ( EZH2 , NUSAP1 , TTK and UBE2C ) were identified, and related prognostic information was obtained. The coexpressed genes of the hub gene set were further screened, and the analysis identified many genes related to the cell cycle. Subsequently, LUAD cell models with TP53 and RB1 inactivation and overexpression of ASCL1 were constructed, and then the expression of hub genes was detected, the results showed that the four hub genes were all elevated in the established cell model.

CONCLUSION: EZH2 , NUSAP1 , TTK and UBE2C may affect the transformation of LUAD to SCLC and represent new candidate molecular markers for the occurrence and development of SCLC.