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Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation Is Dependent on Constitutive Epidermal Growth Factor Receptor Activation

Authors' Affiliations: ¹ Institut National de la Sante et de la Recherche Medicale, EMI 03-37, Faculté de Médecine, Université Paris XII; ² Service d'Urologie, AP-HP Henri Mondor, Créteil, France; ³ Département de biologie, Université libanaise, Hadath, Liban; ⁴ Department of Pathology, Erasmus University, Rotterdam, the Netherlands; ⁵ Service d'Urologie, CHRU, Besançon, France; ⁶ Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada; and ⁷ Centre National de la Recherche Scientifique UMR 144, Institut Curie, Paris, France

Requests for reprints: Gaëlle Nicolle, Institut National de la Sante et de la Recherche Medicale, EMI 03-37, Faculté de Médecine, Université Paris XII, 8 rue du Général Sarrail, 94010 Créteil Cedex, France. Phone: 33-1-498-13656; Fax: 33-1-498-13533; E-mail: gaelle_nicolle{at}yahoo.fr.

Purpose: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC.

Experimental Design: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC.

Results: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens.

Conclusions: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.

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