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ID 53004
FullText URL
Author
Ochi, Nobuaki
Takigawa, Nagio
Harada, Daijiro
Yasugi, Masayuki
Ichihara, Eiki
Hotta, Katsuyuki Kaken ID researchmap
Kiura, Katsuyuki Kaken ID researchmap
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.
File Version
author
Refereed
True
DOI
Web of Science KeyUT