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Cell Cycle, Cell Death, and Senescence

Sensitivity of Normal, Paramalignant, and Malignant Human Urothelial Cells to Inhibitors of the Epidermal Growth Factor Receptor Signaling Pathway

¹ Jack Birch Unit for Molecular Carcinogenesis, University of York, York, United Kingdom and ² GlaxoSmithKline, Safety Assessment, Ware, Hertfordshire, United Kingdom

Requests for reprints: Jennifer Southgate, Jack Birch Unit for Molecular Carcinogenesis, University of York, York YO10 5YW, United Kingdom. Phone: 44-1904328705; Fax: 44-1904328704. E-mail: js35{at}york.ac.uk

Bladder cancer evolves via the accumulation of numerous genetic alterations, with loss of p53 and p16 function representing key events in the development of malignant disease. In addition, components of the epidermal growth factor receptor (EGFR) signaling pathway are frequently overexpressed, providing potential chemotherapeutic targets. We have previously described the generation of "paramalignant" human urothelial cells with disabled p53 or p16 functions. In this study, we investigated the relative responses of normal, paramalignant, and malignant human urothelial cells to EGFR tyrosine kinase inhibitors (PD153035 and GW572016), a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase (MEK) inhibitor (U0126), and a phosphatidylinositol 3-kinase inhibitor (LY294002). The proliferation of normal human urothelial cells was dependent on signaling via the EGFR and MEK pathways and was abolished reversibly by inhibitors of EGFR or downstream MEK signaling pathways. Inhibitors of phosphatidylinositol 3-kinase resulted in only transient cytostasis, which was most likely mediated via cross-talk with the MEK pathway. These responses were maintained in cells with disabled p16 function, whereas cells with loss of p53 function displayed reduced sensitivity to PD153035 and malignant cell lines were the most refractory to PD153035 and U0126. These results indicate that urothelial cells acquire insensitivity to inhibitors of EGFR signaling pathways as a result of malignant transformation. This has important implications for the use of EGFR inhibitors for bladder cancer therapy, as combination treatments with conventional chemotherapy or radiotherapy may protect normal cells and enable better selective targeting of malignant cells. (Mol Cancer Res 2008;6(1):53–63)