This Article Full Text Full Text (PDF) Supplementary Data 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 Kassouf, W. Articles by Adam, L. Search for Related Content PubMed PubMed Citation Articles by Kassouf, W. Articles by Adam, L.

Uncoupling between Epidermal Growth Factor Receptor and Downstream Signals Defines Resistance to the Antiproliferative Effect of Gefitinib in Bladder Cancer Cells

Departments of ¹ Urology and ² Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Department of Cancer Biology, Leonard and Madlyn Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Liana Adam, University of Texas M.D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: ladam{at}mdanderson.org.

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways, such as phosphatidylinositol-3 kinase/Akt and Ras/mitogen-activated protein kinase (MAPK), have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the urogenital tumors. To investigate the mechanism of resistance to EGFR inhibition in bladder cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-3ß (GSK-3ß). We found that the resistance to the antiproliferative effects of gefitinib, in vitro as well as in vivo in nude mice models, was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-3ß activation and degradation of its target cyclin D1 were indicators of a high cell sensitivity to gefitinib. Further analysis of one phenotypic sensitive (253J B-V) and resistant (UM-UC13) cell lines revealed that platelet-derived growth factor receptor-ß (PDGFRß) activation was responsible for short circuiting the EGFR/MAPK pathway for mitogenic stimuli. However, invasion as well as actin dynamics were efficiently reduced by EGFR inhibition in UM-UC13. Chemical disruption of signaling pathways or of PDGFR kinase activity significantly reduced the inactive pool of cellular GSK-3ß in UM-UC13 cells. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in bladder cancer. Although this uncoupling may arise through different mechanisms, we suggest that the resistance of bladder cancer cells to EGFR blockade can be predicted early in the course of treatment by measuring the activation of GSK-3ß and of nuclear cyclin D1.

This article has been cited by other articles:

				P. C. Black, G. A. Brown, T. Inamoto, M. Shrader, A. Arora, A. O. Siefker-Radtke, L. Adam, D. Theodorescu, X. Wu, M. F. Munsell, et al. Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells Clin. Cancer Res., March 1, 2008; 14(5): 1478 - 1486. [Abstract] [Full Text] [PDF]

				C. Sampaio, M. Dance, A. Montagner, T. Edouard, N. Malet, B. Perret, A. Yart, J.-P. Salles, and P. Raynal Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition Mol. Cell. Biol., January 15, 2008; 28(2): 587 - 600. [Abstract] [Full Text] [PDF]

				P. Timpson, A. S. Wilson, G. M. Lehrbach, R. L. Sutherland, E. A. Musgrove, and R. J. Daly Aberrant Expression of Cortactin in Head and Neck Squamous Cell Carcinoma Cells Is Associated with Enhanced Cell Proliferation and Resistance to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Cancer Res., October 1, 2007; 67(19): 9304 - 9314. [Abstract] [Full Text] [PDF]

				F. Perabo and S. Muller New agents for treatment of advanced transitional cell carcinoma Ann. Onc., May 1, 2007; 18(5): 835 - 843. [Abstract] [Full Text] [PDF]

				M. Shrader, M. S. Pino, L. Lashinger, M. Bar-Eli, L. Adam, C. P.N. Dinney, and D. J. McConkey Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Cancer Res., February 15, 2007; 67(4): 1430 - 1435. [Abstract] [Full Text] [PDF]

				W. Yang, Y. Zhang, Y. Li, Z. Wu, and D. Zhu Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3beta Pathway and Is Antagonized by Insulin-like Growth Factor 1 J. Biol. Chem., February 9, 2007; 282(6): 3799 - 3808. [Abstract] [Full Text] [PDF]

				M. Shrader, M. S. Pino, G. Brown, P. Black, L. Adam, M. Bar-Eli, C. P.N. Dinney, and D. J. McConkey Molecular correlates of gefitinib responsiveness in human bladder cancer cells Mol. Cancer Ther., January 1, 2007; 6(1): 277 - 285. [Abstract] [Full Text] [PDF]

				A. Papageorgiou, A. Kamat, W. F. Benedict, C. Dinney, and D. J. McConkey Combination therapy with IFN-{alpha} plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells Mol. Cancer Ther., December 1, 2006; 5(12): 3032 - 3041. [Abstract] [Full Text] [PDF]

				K. N. Blehm, P. E. Spiess, J. E. Bondaruk, M. E. Dujka, G. J. Villares, Y.-j. Zhao, O. Bogler, K. D. Aldape, H. B. Grossman, L. Adam, et al. Mutations Within the Kinase Domain and Truncations of the Epidermal Growth Factor Receptor Are Rare Events in Bladder Cancer: Implications for Therapy Clin. Cancer Res., August 1, 2006; 12(15): 4671 - 4677. [Abstract] [Full Text] [PDF]