期刊
EXPERIMENTAL CELL RESEARCH
卷 322, 期 1, 页码 168-177出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2014.01.007
关键词
EGFR; Src; ERK; Lung cancer; Gefitinib; Resistance
资金
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [24591182, 23390221]
- Kawasaki Medical School [23B-53]
- Grants-in-Aid for Scientific Research [23390221, 24591182] Funding Source: KAKEN
To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)1-(3-pyridy1)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance. (c) 2014 Elsevier Inc. All rights reserved.
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