このエントリーをはてなブックマークに追加
ID 50629
FullText URL
Author
Harada, Daijiro
Takigawa, Nagio
Ochi, Nobuaki
Ninomiya, Takashi
Yasugi, Masayuki
Kubo, Toshio
Takeda, Hiromasa
Ichihara, Eiki Kaken ID publons
Ohashi, Kadoaki
Takata, Saburo
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 612 similar to months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 312 similar to h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.(Cancer Sci, doi: 10.1111/j.1349-7006.2012.02363.x, 2012)
Published Date
2012-10
Publication Title
Cancer Science
Volume
volume103
Issue
issue10
Start Page
1795
End Page
1802
ISSN
1347-9032
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1111/j.1349-7006.2012.02363.x
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/50679
language
英語
File Version
author
Refereed
True
DOI
Web of Science KeyUT