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Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Authors' Affiliations: Departments of ¹ Urology, ² Cancer Biology, ³ Genitourinary Medical Oncology, ⁴ Epidemiology, and ⁵ Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ⁶ Department of Urology, University of Virginia Health System, Charlottesville, Virginia

Requests for reprints: Colin P.N. Dinney, Department of Urology, The University of Texas M. D. Anderson Cancer Center, Unit 1373, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3250; Fax: 713-794-4784; E-mail: cdinney{at}mdanderson.org.

Purpose: Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of urothelial carcinoma, but a clinical response can be expected in only a small proportion of patients. The aim of this study was to define molecular markers of response to cetuximab therapy in a panel of urothelial carcinoma cell lines.

Experimental Design: Eleven cell lines were investigated for antiproliferative response to cetuximab based on [³H]thymidine incorporation. A variety of markers, including EGFR expression, phosphorylation, and gene amplification, as well as the expression of other growth factor receptors, their ligands, and markers of epithelial-to-mesenchymal transition were investigated. Cohen's statistic was used to estimate the agreement between response and expression of these markers. E-cadherin was silenced by small interfering RNA in two sensitive cell lines, and the effect on the response to cetuximab was measured.

Results: We were able to identify a panel of relevant markers pertaining especially to alternate growth factor receptor expression and epithelial-to-mesenchymal transition that predicted response to cetuximab. The data suggested that expression of intact HER-4 (, 1.00; P = 0.008), E-cadherin (, 0.81; P = 0.015), and β-catenin (, 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor β (, 0.57; P = 0.167) were associated with response to cetuximab therapy. Silencing E-cadherin in two sensitive cell lines reduced responsiveness to cetuximab in both (P < 0.001).

Conclusions: A panel of predictive markers for cetuximab response has been established in vitro and is currently being evaluated in a prospective clinical trial of neoadjuvant EGFR-targeted therapy. Most importantly, E-cadherin seems to play a central role in modulation of EGFR response in urothelial carcinoma.