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ID 52842
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Author
Murakami, Toshi
Takigawa, Nagio
Ninomiya, Takashi
Ochi, Nobuaki
Yasugi, Masaaki
Honda, Yoshihiro
Ichihara, Eiki
Abstract
Objective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MIT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model: Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1 mm) in the AZD1480-treated group and control group were 0.37 +/- 0.18 and 2.25 +/- 0.53 (p <0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p <0.0001). Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGER mutation.
Keywords
Lung cancer
Oncogene addiction
EGFR
JAK2
STAT3
Transgenic mice
Published Date
2014-01
Publication Title
Lung Cancer
Volume
volume83
Issue
issue1
Publisher
Elsevier Ireland Ltd.
Start Page
30
End Page
36
ISSN
0169-5002
NCID
AA10785743
Content Type
Journal Article
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/52825
language
英語
Copyright Holders
(C) 2013 Elsevier Ireland Ltd. All rights reserved.
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author
Refereed
True
DOI
Web of Sience KeyUT