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ID 53004
フルテキストURL
著者
Ochi, Nobuaki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Takigawa, Nagio Kawasaki Hosp, Kawasaki Med Sch, Dept Gen Internal Med 4
Harada, Daijiro Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Yasugi, Masayuki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Ichihara, Eiki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Hotta, Katsuyuki Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Tabata, Masahiro Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Tanimoto, Mitsune Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Hematol Oncol & Resp Med
Kiura, Katsuyuki Okayama Univ Hosp, Dept Resp Med
抄録
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.
キーワード
EGFR
Src
ERK
Lung cancer
Gefitinib
Resistance
発行日
2014-03-10
出版物タイトル
Experimental Cell Research
322巻
1号
開始ページ
168
終了ページ
177
ISSN
0014-4827
資料タイプ
学術雑誌論文
関連URL
http://ousar.lib.okayama-u.ac.jp/metadata/52960
言語
English
著作権者
(c) 2014 Elsevier Inc. All rights reserved.
論文のバージョン
author
査読
有り
DOI
Web of Sience KeyUT