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

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

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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 1μM 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 (∼72. h). 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 (∼12. h) 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.

Original languageEnglish
Pages (from-to)150-159
Number of pages10
JournalCancer Letters
Volume296
Issue number2
DOIs
Publication statusPublished - 2010 Oct 1

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Non-Small Cell Lung Carcinoma
Cycloheximide
Phosphatidylinositol 3-Kinases
PTEN Phosphohydrolase
Protein Synthesis Inhibitors
gefitinib
Cetuximab
Protein-Tyrosine Kinases
Transfection
Monoclonal Antibodies
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Sun Mi ; Kim, Ji Su ; Kim, Joo Hang ; Yun, Chae Ok ; Kim, Eun Mi ; Kim, Hyun Ki ; Solca, Flavio ; Choi, Soo Young ; Cho, Byoung Chul. / Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. In: Cancer Letters. 2010 ; Vol. 296, No. 2. pp. 150-159.
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Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. / Kim, Sun Mi; Kim, Ji Su; Kim, Joo Hang; Yun, Chae Ok; Kim, Eun Mi; Kim, Hyun Ki; Solca, Flavio; Choi, Soo Young; Cho, Byoung Chul.

In: Cancer Letters, Vol. 296, No. 2, 01.10.2010, p. 150-159.

Research output: Contribution to journalArticle

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AU - Kim, Sun Mi

AU - Kim, Ji Su

AU - Kim, Joo Hang

AU - Yun, Chae Ok

AU - Kim, Eun Mi

AU - Kim, Hyun Ki

AU - Solca, Flavio

AU - Choi, Soo Young

AU - Cho, Byoung Chul

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AB - 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 1μM 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 (∼72. h). 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 (∼12. h) 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.

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