| Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. | |
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MedLine Citation:
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PMID: 20028874 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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One arising challenge in the treatment of breast cancer is the development of therapeutic resistance to trastuzumab, an antibody targeting the human epidermal growth factor receptor-2 (HER2), which is frequently amplified in breast cancers. In this study, we provide evidence that elevated level of the receptor tyrosine kinase Eph receptor A2 (EphA2) is an important contributor to trastuzumab resistance. In a screen of a large cohort of human breast cancers, we found that EphA2 overexpression correlated with a decrease in disease-free and overall survival of HER2-overexpressing patients. Trastuzumab-resistant cell lines overexpressed EphA2, whereas inhibiting EphA2 restored sensitivity to trastuzumab treatment in vivo. Notably, trastuzumab treatment could promote EphA2 phosphorylation by activating Src kinase, leading in turn to an amplification of phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signaling in resistant cells. Our findings offer mechanistic insights into the basis for trastuzumab resistance and rationalize strategies to target EphA2 as a tactic to reverse trastuzumab resistance. |
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Authors:
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Guanglei Zhuang; Dana M Brantley-Sieders; David Vaught; Jian Yu; Lu Xie; Sam Wells; Dowdy Jackson; Rebecca Muraoka-Cook; Carlos Arteaga; Jin Chen |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2009-12-22 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-01-05 Completed Date: 2010-01-26 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 299-308 Citation Subset: IM |
Affiliation:
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Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tenessee 37232, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibodies, Monoclonal / therapeutic use* Antineoplastic Agents / therapeutic use* Blotting, Western Breast Neoplasms / drug therapy, enzymology*, genetics Cell Line, Tumor Drug Resistance, Neoplasm / genetics* Female Humans Mice Mice, Nude Receptor, EphA2 / biosynthesis*, genetics Receptor, erbB-2 / biosynthesis, genetics Signal Transduction / drug effects Survival Analysis Xenograft Model Antitumor Assays src-Family Kinases / drug effects, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA114301/CA/NCI NIH HHS; CA1179151/CA/NCI NIH HHS; CA95004/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/Antineoplastic Agents; 0/HER2 protein, human; 0/trastuzumab; EC 2.7.10.1/Receptor, EphA2; EC 2.7.10.1/Receptor, erbB-2; EC 2.7.10.2/src-Family Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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