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High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer

W Jeffrey Petty1, William R Voelzke, James J Urbanic

  • 1Department of Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA. wpetty@wfubmc.edu

Lung Cancer (Amsterdam, Netherlands)
|May 11, 2011
PubMed
Abstract

Insights

High cyclin D3 expression confers resistance to erlotinib, a tyrosine kinase inhibitor. Cyclin D3 may serve as a predictive biomarker for erlotinib resistance in cancer patients.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are crucial in cancer therapy.
  • Cyclin D1 was previously identified as a biomarker for TKI response.
  • This study investigates the roles of cyclin D1, D3, and E in erlotinib resistance.

Purpose of the Study:

  • To determine the role of G1 cyclins (D1, D3, E) in mediating sensitivity or resistance to erlotinib.
  • To evaluate cyclin D3 as a potential biomarker for predicting erlotinib resistance.

Main Methods:

  • Transfection of G1 cyclin expression plasmids into NIH 3T3 cells to assess erlotinib sensitivity.
  • Comparison of G1 cyclin expression in erlotinib-sensitive and resistant lung cancer cell lines.
  • Analysis of cyclin D3 expression in patient tumor biopsies before and after erlotinib treatment.

Main Results:

  • Transfection of cyclin D1, D3, or E reduced erlotinib sensitivity in NIH 3T3 cells.
  • Erlotinib-resistant cells exhibited high basal cyclin D3 mRNA and protein levels.
  • Increased cyclin D3 expression was observed in patient tumors post-erlotinib treatment (P=.02).
  • Cyclin D3 transfection into sensitive cells inhibited erlotinib's effects.

Conclusions:

  • High cyclin D3 expression confers resistance to erlotinib both in vitro and in vivo.
  • Cyclin D3 immunohistochemical staining is a promising biomarker for predicting erlotinib resistance.

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