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ID 52033
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Author
Ninomiya, Takashi
Takigawa, Nagio
Ichihara, Eiki
Ochi, Nobuaki
Murakami, Toshi
Honda, Yoshihiro
Kubo, Toshio
Minami, Daisuke
Kudo, Kenichiro
Kiura, Katsuyuki Kakenhi
Abstract
An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation.
Published Date
2013-05
Publication Title
Molecular Cancer Therapeutics
Volume
volume12
Issue
issue5
Publisher
Amer Assoc Cancer Research
Start Page
589
End Page
597
ISSN
1535-7163
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1158/1535-7163.MCT-12-0885
Related Url
http://ousar.lib.okayama-u.ac.jp/metadata/51964
language
英語
Copyright Holders
©2013 American Association for Cancer Research.
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Refereed
True
DOI
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