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Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation

Gain-of-function mutations in the RAS and FLT3 genes are frequently found in cells of acute myeloid leukemia (AML), leading to constitutive activation of signaling pathways that regulate fundamental cellular processes, and are therefore attractive targets for AML therapy. The multi-targeted kinase i...

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Autores principales: Fouladi, Fariba, Jehn, Lutz B., Metzelder, Stephan K., Hub, Florian, Henkenius, Katharina, Burchert, Andreas, Brendel, Cornelia, Stiewe, Thorsten, Neubauer, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732463/
https://www.ncbi.nlm.nih.gov/pubmed/25665465
http://dx.doi.org/10.3109/10428194.2014.1003055
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author Fouladi, Fariba
Jehn, Lutz B.
Metzelder, Stephan K.
Hub, Florian
Henkenius, Katharina
Burchert, Andreas
Brendel, Cornelia
Stiewe, Thorsten
Neubauer, Andreas
author_facet Fouladi, Fariba
Jehn, Lutz B.
Metzelder, Stephan K.
Hub, Florian
Henkenius, Katharina
Burchert, Andreas
Brendel, Cornelia
Stiewe, Thorsten
Neubauer, Andreas
author_sort Fouladi, Fariba
collection PubMed
description Gain-of-function mutations in the RAS and FLT3 genes are frequently found in cells of acute myeloid leukemia (AML), leading to constitutive activation of signaling pathways that regulate fundamental cellular processes, and are therefore attractive targets for AML therapy. The multi-targeted kinase inhibitor sorafenib is efficacious in AML with FLT3-internal tandem duplication (ITD), but resistance to therapy is an important clinical problem. It is unclear whether AML lacking FLT3-ITD responds to sorafenib. Using AML cell lines, we have shown that a low concentration of sorafenib induces opposing effects depending on the oncogenic background. In FLT3-ITD positive cells sorafenib blocks Erk activity and cell proliferation, and triggers apoptosis. However, in cells lacking FLT3-ITD, sorafenib paradoxically activates Erk2, and stimulates cellular proliferation and metabolic activity. Thus, depending on the genetic context, sorafenib is a beneficial inhibitor or paradoxical activator of mitogenic signaling pathways in AML. These results harbor important consequences in planning clinical trials in AML.
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spelling pubmed-47324632016-02-16 Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation Fouladi, Fariba Jehn, Lutz B. Metzelder, Stephan K. Hub, Florian Henkenius, Katharina Burchert, Andreas Brendel, Cornelia Stiewe, Thorsten Neubauer, Andreas Leuk Lymphoma Original Articles: Research Gain-of-function mutations in the RAS and FLT3 genes are frequently found in cells of acute myeloid leukemia (AML), leading to constitutive activation of signaling pathways that regulate fundamental cellular processes, and are therefore attractive targets for AML therapy. The multi-targeted kinase inhibitor sorafenib is efficacious in AML with FLT3-internal tandem duplication (ITD), but resistance to therapy is an important clinical problem. It is unclear whether AML lacking FLT3-ITD responds to sorafenib. Using AML cell lines, we have shown that a low concentration of sorafenib induces opposing effects depending on the oncogenic background. In FLT3-ITD positive cells sorafenib blocks Erk activity and cell proliferation, and triggers apoptosis. However, in cells lacking FLT3-ITD, sorafenib paradoxically activates Erk2, and stimulates cellular proliferation and metabolic activity. Thus, depending on the genetic context, sorafenib is a beneficial inhibitor or paradoxical activator of mitogenic signaling pathways in AML. These results harbor important consequences in planning clinical trials in AML. Taylor & Francis 2015-09-02 2015-03-03 /pmc/articles/PMC4732463/ /pubmed/25665465 http://dx.doi.org/10.3109/10428194.2014.1003055 Text en © 2015 Informa UK Ltd. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article distributed under the terms of the (http://creativecommons.org/licenses/by-nc-nd/3.0/) CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited.
spellingShingle Original Articles: Research
Fouladi, Fariba
Jehn, Lutz B.
Metzelder, Stephan K.
Hub, Florian
Henkenius, Katharina
Burchert, Andreas
Brendel, Cornelia
Stiewe, Thorsten
Neubauer, Andreas
Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title_full Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title_fullStr Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title_full_unstemmed Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title_short Sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking FLT3-ITD mutation
title_sort sorafenib induces paradoxical phosphorylation of the extracellular signal-regulated kinase pathway in acute myeloid leukemia cells lacking flt3-itd mutation
topic Original Articles: Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732463/
https://www.ncbi.nlm.nih.gov/pubmed/25665465
http://dx.doi.org/10.3109/10428194.2014.1003055
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