Title:An Integrative Analysis of the Putative Gefitinib-resistance Related Genes in a Lung Cancer Cell Line Model System
Volume: 15
Issue: 5
Author(s): Xiaohong Han, Manjiao Liu, Shuai Wang, Guanting Lv, Li Ma, Changqing Zeng and Yuankai Shi
Affiliation:
Keywords:
CNAs, DEGs, drug resistance, EGFR kinase inhibitor, lung cancer, SNVs, transcriptome, .
Abstract: The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKI),
such as gefitinib and erlotinib have improved the survival of patients with nonsmall
cell lung cancer (NSCLC). Unfortunately, acquired resistance will eventually
develop in most patients who initially respond to the therapy. Currently known molecular mechanisms for such an
acquired resistance may interpret only about 70% of clinical cases. In this study, using NSCLC cell model H1650, we
constructed a gefitinib resistant cell line H1650GR through long term drug exposure with increased doses. RNA
sequencing and whole genome SNP array were applied to investigate the transcriptome and genome alterations possibly
involved in gefitinib resistance. By comparing the expression profiles between H1650GR and H1650 cells, we identified a
large set of differentially expressed genes (DEGs), including FOXM1. In the PI3K/AKT pathway, AKT activity was
predicted to be inhibited. However, genes that play important roles in gefitinib-induced apoptosis, including TP53,
FOXO3 and BAD, were not up-regulated. Ingenuity Pathway Analysis (IPA) canonical pathway analysis showed that p53
signaling was inhibited in H1650GR cells, with down-regulation of pro-apoptosis genes FAS, PUMA, NOXA, and upregulation
of anti-apoptosis genes BIRC5/Survivin. Besides, a large number of immune response-related genes were
differently expressed, the role of which in gefitinib resistance requires further investigation. Whole genome copy number
alterations (CNAs) were also analyzed and NOXA was located in the H1650GR unique copy number loss region, 18q21.
Our results suggested that the much higher EGFR-TKI resistance in H1650GR may be produced by the integration of
multi-aspect factors.
