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Int. J. Mol. Sci. 2014, 15(11), 20500-20517; doi:10.3390/ijms151120500

Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer

1
Department of Urology, Heinrich-Heine-University, Moorenstr. 5, Düsseldorf D-40225, Germany
2
Helmholtz-Zentrum für Infektionsforschung, Inhoffenstr. 7, Braunschweig D-38124, Germany
3
Institute for Molecular and Clinical Immunology, Otto-von-Guericke-University, Leipzigerstr. 44, Magdeburg D-39120, Germany
*
Author to whom correspondence should be addressed.
Received: 25 September 2014 / Revised: 30 October 2014 / Accepted: 30 October 2014 / Published: 7 November 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor α/-receptor β, PDGFR-α/-β; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma. View Full-Text
Keywords: tyrosine kinase inhibitor; urothelial cancer; mitogen activated protein kinase (MAPK) signaling; apoptosis tyrosine kinase inhibitor; urothelial cancer; mitogen activated protein kinase (MAPK) signaling; apoptosis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Knievel, J.; Schulz, W.A.; Greife, A.; Hader, C.; Lübke, T.; Schmitz, I.; Albers, P.; Niegisch, G. Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer. Int. J. Mol. Sci. 2014, 15, 20500-20517.

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