| Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. | |
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MedLine Citation:
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PMID: 18599154 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Epithelial to mesenchymal transition (EMT) has been reported to be related with reduced sensitivity to EGFR tyrosine kinase (EGFR-TK) inhibitors. We performed this study to investigate whether this phenomenon would play a role in acquired resistance to gefitinib. In this study, we established a gefitinib-resistant subline (A549/GR), which was derived from the parental A549 cell line by chronic, repeated exposure to gefitinib. Compared with the A549 cells, the A549/GR cells were approximately 7.7-fold more resistant to gefitinib and they showed the cross-resistance against other EGFR-TK inhibitors, including CL-387,758, erlotinib and ZD6478. Phenotypic changes such as a spindle-cell shape and increased pseudopodia formation suggesting EMT was present in the A549/GR cells. These changes were accompanied by a decrease of E-cadherin and an increase of vimentin, which is a mesenchymal marker. In addition, the ability of invasion and migration was increased in the A549/GR cells. TGF-beta1 treatment for 72 h also induced EMT in the A549 cells and this transition led to resistance to gefitinib. Conversely, this was reversed through the removal of TGF-beta1. In conclusion, induction of EMT may contribute to the decreased efficacy of therapy in primary and acquired resistance to gefitinib. |
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Authors:
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Jin Kyung Rho; Yun Jung Choi; Jin Kyung Lee; Baek-Yeol Ryoo; Im Il Na; Sung Hyun Yang; Cheol Hyeon Kim; Jae Cheol Lee |
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Publication Detail:
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Type: Journal Article Date: 2008-07-02 |
Journal Detail:
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Title: Lung cancer (Amsterdam, Netherlands) Volume: 63 ISSN: 0169-5002 ISO Abbreviation: Lung Cancer Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-01-06 Completed Date: 2009-03-10 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8800805 Medline TA: Lung Cancer Country: Ireland |
Other Details:
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Languages: eng Pagination: 219-26 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Science, Seoul 139-706, Republic of Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Carcinoma, Non-Small-Cell Lung / drug therapy*, pathology Cell Line, Tumor Cell Movement Drug Resistance, Neoplasm Epithelium / pathology* Humans Lung Neoplasms / drug therapy*, pathology Mesoderm / pathology* Neoplasm Invasiveness Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-akt / metabolism Quinazolines / pharmacology* Receptor, Epidermal Growth Factor / antagonists & inhibitors* Transforming Growth Factor beta1 / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/Transforming Growth Factor beta1; 184475-35-2/gefitinib; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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