2.50
Hdl Handle:
http://hdl.handle.net/10033/338469
Title:
Multiple mechanisms mediate resistance to sorafenib in urothelial cancer.
Authors:
Knievel, Judith; Schulz, Wolfgang A; Greife, Annemarie; Hader, Christiane; Lübke, Tobias; Schmitz, Ingo ( 0000-0002-5360-0419 ) ; Albers, Peter; Niegisch, Günter
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.
Citation:
Multiple mechanisms mediate resistance to sorafenib in urothelial cancer. 2014, 15 (11):20500-17 Int J Mol Sci
Journal:
International journal of molecular sciences
Issue Date:
2014
URI:
http://hdl.handle.net/10033/338469
DOI:
10.3390/ijms151120500
PubMed ID:
25387078
Type:
Article
Language:
en
ISSN:
1422-0067
Appears in Collections:
publications of the central unit for microscopy (ZEIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorKnievel, Judithen
dc.contributor.authorSchulz, Wolfgang Aen
dc.contributor.authorGreife, Annemarieen
dc.contributor.authorHader, Christianeen
dc.contributor.authorLübke, Tobiasen
dc.contributor.authorSchmitz, Ingoen
dc.contributor.authorAlbers, Peteren
dc.contributor.authorNiegisch, Günteren
dc.date.accessioned2015-01-15T14:56:52Zen
dc.date.available2015-01-15T14:56:52Zen
dc.date.issued2014en
dc.identifier.citationMultiple mechanisms mediate resistance to sorafenib in urothelial cancer. 2014, 15 (11):20500-17 Int J Mol Scien
dc.identifier.issn1422-0067en
dc.identifier.pmid25387078en
dc.identifier.doi10.3390/ijms151120500en
dc.identifier.urihttp://hdl.handle.net/10033/338469en
dc.description.abstractGenetic 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.en
dc.language.isoenen
dc.titleMultiple mechanisms mediate resistance to sorafenib in urothelial cancer.en
dc.typeArticleen
dc.identifier.journalInternational journal of molecular sciencesen

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