Abstract:
:Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Saito K,Takigawa N,Ohtani N,Iioka H,Tomita Y,Ueda R,Fukuoka J,Kuwahara K,Ichihara E,Kiura K,Kondo Edoi
10.1158/1535-7163.MCT-12-1239subject
Has Abstractpub_date
2013-08-01 00:00:00pages
1616-28issue
8eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-12-1239journal_volume
12pub_type
杂志文章abstract::Preclinical data suggest that combined EGF receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non-small cell lung cancer treated with the co...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-1208
更新日期:2013-10-01 00:00:00
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更新日期:2008-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0763
更新日期:2011-04-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0424
更新日期:2011-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0018
更新日期:2006-06-01 00:00:00
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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-11-0535
更新日期:2012-08-01 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:2005-01-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0431
更新日期:2019-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0982
更新日期:2018-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0305
更新日期:2015-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0492
更新日期:2013-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2018-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0408
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0798
更新日期:2013-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-11-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0945
更新日期:2019-07-01 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:2011-08-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-1169
更新日期:2010-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:2013-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 临床试验,杂志文章
doi:10.1158/1535-7163.MCT-08-0411
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-09-0191
更新日期:2009-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0491
更新日期:2008-01-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0318
更新日期:2020-02-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-1334
更新日期:2019-11-01 00:00:00