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Int J Clin Exp Pathol 2013;6(8):1493-1504

Original Article
RAF1-MEK1-ERK/AKT axis may confer NSCLC cell lines resistance to erlotinib

Zhi-Hong Xu, Jun-Biao Hang, Jia-An Hu, Bei-Li Gao

Department of Geriatrics, Ruijin Hospital affiliated to Shanghai JiaoTong University, Shanghai, China; Department of Thoracic surgery, Ruijin
Hospital affiliated to Shanghai JiaoTong University, Shanghai, China; Department of Respiratory, Ruijin Hospital affiliated to Shanghai
JiaoTong University, Shanghai, China

Received June 20, 2013; Accepted July 5, 2013; Epub July 15, 2013; Published August 1, 2013

Abstract: The fact that advanced NSCLC patients with wild type (wt) EGFR can benefit from erlotinib therapy makes it critical to find out
biomarkers for effective selection of patients and improving the therapy effects. In present study, 3 NSCLC cell lines (U1752, Calu-6 and NCI-
H292) with wt EGFR and different sensitivities to erlotinib were used for microarray analysis. The differential basal gene expression between 2
NSCLC cell lines was analyzed, about 353 genes were expression-altered with higher than 2-fold changes between Calu-6 and U1752. And
Ingenuity Pathway Analysis (IPA) showed that these genes were mainly enriched in regulation of epithelial–mesenchymal transition (EMT)
pathway, Wnt-β catenin signaling, Tec kinase signaling and some types of cancer-related signaling. More interestingly, RAF1 (c-raf), MAP2K1
(MEK1), SNAI and downstream signaling molecules ERK and AKT were predicted to be activated in erlotinib-resistant cell line by IPA.
Subsequent immunoblotting experiments showed that the phosphorylation of ERK and AKT were exactly increased stepwise from erlotinib
sensitive cell line to erlotinib resistant cell lines. Collectively, activation of RAF1-MEK1-ERK/AKT axis may determine the resistance of NSCLC
cell lines bearing wt EGFR to erlotinib. Our work provides potential biomarkers and therapeutic targets for NSCLC patients harboring wt EGFR.
(IJCEP1306018).

Keywords: Non-small cell lung cancer, NSCLC, EGFR, erlotinib, microarray, RAF1, MAP2K1, ERK, AKT

Address correspondence to: Dr. Bei-Li Gao and Jia-An Hu, Department of Respiratory and Department of Geriatrics, respectively, Ruijin
Hospital affiliated to Shanghai JiaoTong University, Shanghai, China. E-mail: gaobeili_ruijin@163.com; jahu_rj@aliyun.com