Cited 45 times in
Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells.
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 김선미 | - |
dc.contributor.author | 김주항 | - |
dc.contributor.author | 김지수 | - |
dc.contributor.author | 김현기 | - |
dc.contributor.author | 윤채옥 | - |
dc.contributor.author | 조병철 | - |
dc.contributor.author | 최수영 | - |
dc.date.accessioned | 2015-04-23T16:58:15Z | - |
dc.date.available | 2015-04-23T16:58:15Z | - |
dc.date.issued | 2010 | - |
dc.identifier.issn | 0304-3835 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/101578 | - |
dc.description.abstract | EGFR 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.statementOfResponsibility | open | - |
dc.format.extent | 150~159 | - |
dc.relation.isPartOf | CANCER LETTERS | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.subject.MESH | Antibodies, Monoclonal/therapeutic use* | - |
dc.subject.MESH | Antibodies, Monoclonal, Humanized | - |
dc.subject.MESH | Antineoplastic Agents/therapeutic use | - |
dc.subject.MESH | Carcinoma, Non-Small-Cell Lung/drug therapy* | - |
dc.subject.MESH | Carcinoma, Non-Small-Cell Lung/pathology | - |
dc.subject.MESH | Cell Line, Tumor | - |
dc.subject.MESH | Cell Survival/drug effects | - |
dc.subject.MESH | Cetuximab | - |
dc.subject.MESH | DNA Primers | - |
dc.subject.MESH | Drug Resistance, Neoplasm* | - |
dc.subject.MESH | Flow Cytometry | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Lung Neoplasms/drug therapy* | - |
dc.subject.MESH | PTEN Phosphohydrolase/genetics* | - |
dc.subject.MESH | PTEN Phosphohydrolase/metabolism | - |
dc.subject.MESH | Quinazolines/therapeutic use* | - |
dc.subject.MESH | RNA, Small Interfering/genetics | - |
dc.subject.MESH | Receptor, Epidermal Growth Factor/metabolism | - |
dc.subject.MESH | Reverse Transcriptase Polymerase Chain Reaction | - |
dc.subject.MESH | Transfection | - |
dc.title | Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Life Science (의생명과학부) | - |
dc.contributor.googleauthor | Sun Mi Kim | - |
dc.contributor.googleauthor | Ji Su Kim | - |
dc.contributor.googleauthor | Joo-Hang Kim | - |
dc.contributor.googleauthor | Chae-Ok Yun | - |
dc.contributor.googleauthor | Eun Mi Kim | - |
dc.contributor.googleauthor | Hyun Ki Kim | - |
dc.contributor.googleauthor | Flavio Solca | - |
dc.contributor.googleauthor | Soo-Young Choi | - |
dc.contributor.googleauthor | Byoung Chul Cho | - |
dc.identifier.doi | 10.1016/j.canlet.2010.04.006 | - |
dc.admin.author | false | - |
dc.admin.mapping | false | - |
dc.contributor.localId | A00945 | - |
dc.contributor.localId | A01108 | - |
dc.contributor.localId | A02614 | - |
dc.contributor.localId | A03822 | - |
dc.contributor.localId | A04093 | - |
dc.contributor.localId | A00969 | - |
dc.contributor.localId | A00546 | - |
dc.relation.journalcode | J00448 | - |
dc.identifier.eissn | 1872-7980 | - |
dc.identifier.pmid | 20444542 | - |
dc.identifier.url | http://www.sciencedirect.com/science/article/pii/S0304383510002107 | - |
dc.subject.keyword | Cetuximab | - |
dc.subject.keyword | Gefitinib | - |
dc.subject.keyword | Acquired resistance | - |
dc.subject.keyword | PTEN | - |
dc.subject.keyword | Akt | - |
dc.contributor.alternativeName | Kim, Sun Mi | - |
dc.contributor.alternativeName | Kim, Joo Hang | - |
dc.contributor.alternativeName | Kim, Ji Su | - |
dc.contributor.alternativeName | Kim, Hyun Ki | - |
dc.contributor.alternativeName | Yun, Chae Ok | - |
dc.contributor.alternativeName | Cho, Byoung Chul | - |
dc.contributor.alternativeName | Choi, Soo Young | - |
dc.contributor.affiliatedAuthor | Kim, Joo Hang | - |
dc.contributor.affiliatedAuthor | Kim, Hyun Ki | - |
dc.contributor.affiliatedAuthor | Yun, Chae Ok | - |
dc.contributor.affiliatedAuthor | Cho, Byoung Chul | - |
dc.contributor.affiliatedAuthor | Choi, Soo Young | - |
dc.contributor.affiliatedAuthor | Kim, Ji Su | - |
dc.contributor.affiliatedAuthor | Kim, Sun Mi | - |
dc.citation.volume | 296 | - |
dc.citation.number | 2 | - |
dc.citation.startPage | 150 | - |
dc.citation.endPage | 159 | - |
dc.identifier.bibliographicCitation | CANCER LETTERS, Vol.296(2) : 150-159, 2010 | - |
dc.identifier.rimsid | 40100 | - |
dc.type.rims | ART | - |
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