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Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma

Peter C Black1, Gordon A Brown, Teruo Inamoto

  • 1Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 5, 2008
PubMed
Abstract

Insights

Predictive molecular markers for cetuximab response in urothelial carcinoma were identified. E-cadherin expression is crucial for modulating epidermal growth factor receptor (EGFR) targeted therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Epidermal growth factor receptor (EGFR) is a target for urothelial carcinoma treatment.
  • Response rates to EGFR-targeted therapies like cetuximab are limited in urothelial carcinoma.
  • Identifying predictive biomarkers is essential to optimize patient selection for cetuximab therapy.

Purpose of the Study:

  • To define molecular markers that predict response to cetuximab in urothelial carcinoma cell lines.
  • To investigate the role of EGFR pathway components and epithelial-to-mesenchymal transition (EMT) markers in cetuximab sensitivity.
  • To establish an in vitro panel of predictive markers for EGFR-targeted therapy.

Main Methods:

  • Investigated antiproliferative response to cetuximab in eleven urothelial carcinoma cell lines using [(3)H]thymidine incorporation.
  • Assessed EGFR expression, phosphorylation, gene amplification, other growth factor receptors, ligands, and EMT markers.
  • Utilized Cohen's kappa statistic to correlate marker expression with cetuximab response.
  • Performed E-cadherin silencing via small interfering RNA (siRNA) to evaluate its impact on cetuximab response.

Main Results:

  • Identified a panel of markers, including alternate growth factor receptor expression and EMT markers, that predict cetuximab response.
  • Significantly associated markers with cetuximab response include intact HER-4 (kappa=1.00), E-cadherin (kappa=0.81), beta-catenin (kappa=0.81), and loss of platelet-derived growth factor receptor beta (kappa=0.57).
  • Silencing E-cadherin in sensitive cell lines significantly reduced responsiveness to cetuximab (P < 0.001).

Conclusions:

  • Established an in vitro panel of predictive markers for cetuximab response in urothelial carcinoma.
  • These predictive markers are currently being validated in a prospective clinical trial for neoadjuvant EGFR-targeted therapy.
  • E-cadherin plays a critical role in modulating the response to EGFR-targeted therapy in urothelial carcinoma.

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