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Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells.

DC FieldValueLanguage
dc.contributor.author김선미-
dc.contributor.author김주항-
dc.contributor.author김지수-
dc.contributor.author김현기-
dc.contributor.author윤채옥-
dc.contributor.author조병철-
dc.contributor.author최수영-
dc.date.accessioned2015-04-23T16:58:15Z-
dc.date.available2015-04-23T16:58:15Z-
dc.date.issued2010-
dc.identifier.issn0304-3835-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/101578-
dc.description.abstractEGFR inhibitors, including the small-molecule tyrosine kinase inhibitors such as gefitinib, and the monoclonal antibodies directed at the receptor such as cetuximab, have demonstrated promising effects in non-small cell lung cancer (NSCLC). In this study, we generated cetuximab-resistant cell lines (HCC827-CR) from HCC827 NSCLC cells to investigate acquired resistance mechanisms to cetuximab. In HCC827-CR cells, Akt was hyperactivated and its activity was persistent upon cetuximab treatment. Blockade of PI3K/Akt activity restored cetuximab sensitivity in HCC827-CR cells. Further investigation revealed that increased PTEN instability mediates constitutive Akt activation. By 1microM proteosomal inhibitor, MG-132, PTEN protein levels were restored and Akt activity was dramatically reduced. Overexpression of PTEN by transfection could not restore cetuximab sensitivity in HCC827-CR because overexpressed PTEN was degraded rapidly ( approximately 72h). The increased PTEN instability was confirmed by the treatment of HCC827-CR with a protein synthesis inhibitor, cycloheximide. In the presence of cycloheximide, overexpressed PTEN was degraded more rapidly ( approximately 12h) in HCC827-CR cells. Interestingly, HCC827-CR cells also revealed de novo resistance to gefitinib. Inhibition of PI3K/Akt signaling pathway restored sensitivity to gefitinib in HCC827-CR cells. Taken together, these data show that PTEN instability-mediated constitutive Akt activation is involved in acquired resistance mechanisms to cetuximab and also induces de novo resistance to gefitinib. Importantly, these findings suggest emergence of cross-resistance between two agents as a potential serious problem in the clinical setting.-
dc.description.statementOfResponsibilityopen-
dc.format.extent150~159-
dc.relation.isPartOfCANCER LETTERS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAntibodies, Monoclonal/therapeutic use*-
dc.subject.MESHAntibodies, Monoclonal, Humanized-
dc.subject.MESHAntineoplastic Agents/therapeutic use-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/drug therapy*-
dc.subject.MESHCarcinoma, Non-Small-Cell Lung/pathology-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Survival/drug effects-
dc.subject.MESHCetuximab-
dc.subject.MESHDNA Primers-
dc.subject.MESHDrug Resistance, Neoplasm*-
dc.subject.MESHFlow Cytometry-
dc.subject.MESHHumans-
dc.subject.MESHLung Neoplasms/drug therapy*-
dc.subject.MESHPTEN Phosphohydrolase/genetics*-
dc.subject.MESHPTEN Phosphohydrolase/metabolism-
dc.subject.MESHQuinazolines/therapeutic use*-
dc.subject.MESHRNA, Small Interfering/genetics-
dc.subject.MESHReceptor, Epidermal Growth Factor/metabolism-
dc.subject.MESHReverse Transcriptase Polymerase Chain Reaction-
dc.subject.MESHTransfection-
dc.titleAcquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells.-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Life Science (의생명과학부)-
dc.contributor.googleauthorSun Mi Kim-
dc.contributor.googleauthorJi Su Kim-
dc.contributor.googleauthorJoo-Hang Kim-
dc.contributor.googleauthorChae-Ok Yun-
dc.contributor.googleauthorEun Mi Kim-
dc.contributor.googleauthorHyun Ki Kim-
dc.contributor.googleauthorFlavio Solca-
dc.contributor.googleauthorSoo-Young Choi-
dc.contributor.googleauthorByoung Chul Cho-
dc.identifier.doi10.1016/j.canlet.2010.04.006-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA00945-
dc.contributor.localIdA01108-
dc.contributor.localIdA02614-
dc.contributor.localIdA03822-
dc.contributor.localIdA04093-
dc.contributor.localIdA00969-
dc.contributor.localIdA00546-
dc.relation.journalcodeJ00448-
dc.identifier.eissn1872-7980-
dc.identifier.pmid20444542-
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0304383510002107-
dc.subject.keywordCetuximab-
dc.subject.keywordGefitinib-
dc.subject.keywordAcquired resistance-
dc.subject.keywordPTEN-
dc.subject.keywordAkt-
dc.contributor.alternativeNameKim, Sun Mi-
dc.contributor.alternativeNameKim, Joo Hang-
dc.contributor.alternativeNameKim, Ji Su-
dc.contributor.alternativeNameKim, Hyun Ki-
dc.contributor.alternativeNameYun, Chae Ok-
dc.contributor.alternativeNameCho, Byoung Chul-
dc.contributor.alternativeNameChoi, Soo Young-
dc.contributor.affiliatedAuthorKim, Joo Hang-
dc.contributor.affiliatedAuthorKim, Hyun Ki-
dc.contributor.affiliatedAuthorYun, Chae Ok-
dc.contributor.affiliatedAuthorCho, Byoung Chul-
dc.contributor.affiliatedAuthorChoi, Soo Young-
dc.contributor.affiliatedAuthorKim, Ji Su-
dc.contributor.affiliatedAuthorKim, Sun Mi-
dc.citation.volume296-
dc.citation.number2-
dc.citation.startPage150-
dc.citation.endPage159-
dc.identifier.bibliographicCitationCANCER LETTERS, Vol.296(2) : 150-159, 2010-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers

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