TY - JOUR
T1 - Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells
AU - Black, Peter C.
AU - Brown, Gordon A.
AU - Inamoto, Teruo
AU - Shrader, Marissa
AU - Arora, Ameeta
AU - Siefker-Radtke, Arlene O.
AU - Adam, Liana
AU - Theodorescu, Dan
AU - Wu, Xifeng
AU - Munsell, Mark F.
AU - Bar-Eli, Menashe
AU - McConkey, David J.
AU - Dinney, Colin P.N.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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 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.
AB - 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 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.
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U2 - 10.1158/1078-0432.CCR-07-1593
DO - 10.1158/1078-0432.CCR-07-1593
M3 - Article
C2 - 18316572
AN - SCOPUS:40949091867
SN - 1078-0432
VL - 14
SP - 1478
EP - 1486
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -