Nobuaki Ochi    Department   Kawasaki Medical School  Kawasaki Medical School, Department of General Internal Medicine 4,    Position   Assistant Professor
Article types	原著
Language	English
Peer review	Peer reviewed
Title	Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer
Journal	Formal name：Experimental cell research Abbreviation：Exp Cell Res ISSN code：1090-2422
Publisher	Elsevier
Volume, Issue, Page	322(1),pp.168-177
Author and coauthor	Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura
Authorship	Lead author
Publication date	2014/03
Summary	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