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ID 53004
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Author
Ochi, Nobuaki
Takigawa, Nagio
Harada, Daijiro
Yasugi, Masayuki
Ichihara, Eiki
Abstract
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.
Keywords
EGFR
Src
ERK
Lung cancer
Gefitinib
Resistance
Published Date
2014-03-10
Publication Title
Experimental Cell Research
Volume
volume322
Issue
issue1
Start Page
168
End Page
177
ISSN
0014-4827
Content Type
Journal Article
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/52960
language
英語
Copyright Holders
(c) 2014 Elsevier Inc. All rights reserved.
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author
Refereed
True
DOI
Web of Sience KeyUT