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

Authors
 Sun Mi Kim  ;  Ji Su Kim  ;  Joo-Hang Kim  ;  Chae-Ok Yun  ;  Eun Mi Kim  ;  Hyun Ki Kim  ;  Flavio Solca  ;  Soo-Young Choi  ;  Byoung Chul Cho 
Citation
 CANCER LETTERS, Vol.296(2) : 150-159, 2010 
Journal Title
 CANCER LETTERS 
ISSN
 0304-3835 
Issue Date
2010
MeSH
Antibodies, Monoclonal/therapeutic use* ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/therapeutic use ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cetuximab ; DNA Primers ; Drug Resistance, Neoplasm* ; Flow Cytometry ; Humans ; Lung Neoplasms/drug therapy* ; PTEN Phosphohydrolase/genetics* ; PTEN Phosphohydrolase/metabolism ; Quinazolines/therapeutic use* ; RNA, Small Interfering/genetics ; Receptor, Epidermal Growth Factor/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection
Keywords
Cetuximab ; Gefitinib ; Acquired resistance ; PTEN ; Akt
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0304383510002107
DOI
10.1016/j.canlet.2010.04.006
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
Yonsei Authors
Kim, Sun Mi(김선미)
Kim, Joo Hang(김주항)
Kim, Ji Su(김지수)
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Yun, Chae Ok(윤채옥)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Choi, Soo Young(최수영)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/101578
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