Abstract:
:Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Mori M,Ueno Y,Konagai S,Fushiki H,Shimada I,Kondoh Y,Saito R,Mori K,Shindou N,Soga T,Sakagami H,Furutani T,Doihara H,Kudoh M,Kuromitsu Sdoi
10.1158/1535-7163.MCT-13-0395subject
Has Abstractpub_date
2014-02-01 00:00:00pages
329-40issue
2eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-13-0395journal_volume
13pub_type
杂志文章abstract::Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cel...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0209
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 临床试验,杂志文章
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更新日期:2008-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0172
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0967
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0008
更新日期:2016-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0809
更新日期:2011-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2003-08-01 00:00:00
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0013
更新日期:2014-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0005
更新日期:2016-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0298
更新日期:2018-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2004-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-2122
更新日期:2008-03-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0577-T
更新日期:2016-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0149
更新日期:2006-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0403
更新日期:2007-02-01 00:00:00
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2008-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2010-03-01 00:00:00
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更新日期:2016-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
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