オチ　ノブアキ   Nobuaki Ochi   越智　宣昭    所属   川崎医科大学  医学部 臨床医学　総合内科学４    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer
掲載誌名	正式名：Experimental cell research 略　 称：Exp Cell Res ISSNコード：1090-2422
出版社	Elsevier
巻・号・頁	322(1),pp.168-177
著者・共著者	Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura
担当区分	筆頭著者
発行年月	2014/03
概要	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-pyridyl)-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.
DOI	10.1016/j.yexcr.2014.01.007
PMID	24509171