This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Black, P. C. Articles by Dinney, C. P.N. Search for Related Content PubMed PubMed Citation Articles by Black, P. C. Articles by Dinney, C. P.N.

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.

This article has been cited by other articles:

				D. A. Nikolova, I. A. Asangani, L. D. Nelson, D. P.M. Hughes, D. R. Siwak, G. B. Mills, A. Harms, E. Buchholz, L. R. Pilz, C. Manegold, et al. Cetuximab Attenuates Metastasis and u-PAR Expression in Non-Small Cell Lung Cancer: u-PAR and E-Cadherin are Novel Biomarkers of Cetuximab Sensitivity Cancer Res., March 15, 2009; 69(6): 2461 - 2470. [Abstract] [Full Text] [PDF]

				Y. Haddad, W. Choi, and D. J. McConkey Delta-Crystallin Enhancer Binding Factor 1 Controls the Epithelial to Mesenchymal Transition Phenotype and Resistance to the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Human Head and Neck Squamous Cell Carcinoma Lines Clin. Cancer Res., January 15, 2009; 15(2): 532 - 542. [Abstract] [Full Text] [PDF]

				E. Soto, M. Yanagisawa, L. A. Marlow, J. A. Copland, E. A. Perez, and P. Z. Anastasiadis p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression J. Cell Biol., November 18, 2008; 183(4): 737 - 749. [Abstract] [Full Text] [PDF]

				M. S. Pino, M. Balsamo, F. Di Modugno, M. Mottolese, M. Alessio, E. Melucci, M. Milella, D. J. McConkey, U. Philippar, F. B. Gertler, et al. Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines Clin. Cancer Res., August 1, 2008; 14(15): 4943 - 4950. [Abstract] [Full Text] [PDF]