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


ABSTRACT: 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.

SUBMITTER: Fouladi F 

PROVIDER: S-EPMC4732463 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Fouladi Fariba F   Jehn Lutz B LB   Metzelder Stephan K SK   Hub Florian F   Henkenius Katharina K   Burchert Andreas A   Brendel Cornelia C   Stiewe Thorsten T   Neubauer Andreas A  

Leukemia & lymphoma 20150303 9


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  ...[more]

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