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

• Published in: Clinical cancer research Vol. 14; no. 5; pp. 1478 - 1486
• Main Authors: BLACK, Peter C, BROWN, Gordon A, BAR-ELI, Menashe, MCCONKEY, David J, DINNEY, Colin P. N, INAMOTO, Teruo, SHRADER, Marissa, ARORA, Ameeta, SIEFKER-RADTKE, Arlene O, ADAM, Liana, THEODORESCU, Dan, XIFENG WU, MUNSELL, Mark F
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2008
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - secondary; Cell Proliferation - drug effects; Cells, Cultured; Cetuximab; DNA Mutational Analysis; Drug Resistance, Neoplasm; E-cadherin; EGFR; Enzyme-Linked Immunosorbent Assay; Epithelial-to-mesenchymal transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - physiology; Humans; In Situ Hybridization, Fluorescence; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Invasiveness; Nephrology. Urinary tract diseases; NIH 3T3 Cells; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Phenotype; Phosphorylation - drug effects; Receptor, Epidermal Growth Factor - antagonists & inhibitors; RNA, Small Interfering - pharmacology; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Urothelial carcinoma; Urinary system disease; Cell adhesion molecule; Urinary tract disease; Malignant tumor; Bladder carcinoma; Gene expression; Epidermal growth factor receptor; Growth factor receptor; Sensitivity; Bladder disease; Inhibitor; E Cadherin; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1593

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 [ 3 H]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 κ 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 ( κ, 1.00; P = 0.008), E-cadherin ( κ , 0.81; P = 0.015), and β-catenin ( κ , 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor β ( κ , 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.