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

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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

Bibliographical note

Funding Information:
This study was supported by a faculty research grant of Yonsei University College of Medicine for 6-2009-0066. We thank Dr. Alex A. Adjei for thoughtful comments and review of the manuscript.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells'. Together they form a unique fingerprint.

Cite this