AURKA upregulation plays a role in fibroblast-reduced gefitinib sensitivity in the NSCLC cell line HCC827.

Jia Chen,Lishuang Zhu,Yili Yang,Huanxing Han,Huiqi Lu,Chang Liu,Huabin Yin,Huimin Hu,Wang Zhou,Pengfei Zhang

doi:10.3892/or.2015.3764

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat non-small cell lung carcinoma (NSCLC) patients that have EGFR-activating mutations. EGFR-TKI monotherapy in most NSCLC patients with EGFR mutations who initially respond to EGFR-TKIs results in the development of acquired resistance. We investigated the role of fibroblasts in stromal cell-mediated resistance to gefitinib-induced apoptosis in EGFR-mutant NSCLC cells. While gefitinib induced apoptosis in EGFR-mutant NSCLC cells, apoptosis induction was diminished under stromal co-culture conditions. Protection appeared to be mediated in part by Aurora-A kinase (AURKA) upregulation. The protective effect of stromal cells was significantly reduced by pre-exposure to AURKA-shRNA. We suggest that combinations of AURKA antagonists and EGFR inhibitors may be effective in clinical trials targeting mutant EGFR NSCLCs.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide with non-small cell lung carcinoma (NSCLC) accounting for ~80% of lung cancers [1]
We examined the effect of co-culture with fibroblasts on the protection of HCC827 cells from gefitinib-induced apoptosis
We did not find evidence of any increasing protective effect when cells were exposed for longer time periods (24 or 48 h, Fig. 1C). These results suggest that fibroblasts reduce gefitinib sensitivity in lung cancer cells with epidermal growth factor receptor (EGFR)-activating mutations, regardless of the state of the fibroblasts

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide with non-small cell lung carcinoma (NSCLC) accounting for ~80% of lung cancers [1]. Activating mutations of the epidermal growth factor receptor (EGFR) occur in 30-40% of the patients with NSCLC in China, and are associated with poor prognosis [2]. EGFR mutations result in constitutive activation of the EGFR in the absence of the EGF ligand and abnormal activation of downstream signaling pathways, including mitogen-activated protein kinase (Mek)/extracellular signal regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K) [3,4,5]. While most NSCLC patients with EGFR mutations initially respond to EGFR-tyrosine kinase inhibitors (TKIs), acquired resistance develops [13]

Methods

Results

Conclusion