Phosphoproteome Analysis Reveals Differential Mode of Action of Sorafenib in Wildtype and Mutated FLT3 Acute Myeloid Leukemia (AML) Cells

Overview

Journal Mol Cell Proteomics

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2017 Apr 29

PMID 28450419

Citations 6

Authors

Catrin Roolf

Nikolaj Dybowski

Anett Sekora

Stefan Mueller

Gudrun Knuebel

Andreas Tebbe

Hugo Murua Escobar

Klaus Godl

Christian Junghanss

Christoph Schaab

Affiliations

Soon will be listed here.

Abstract

Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, applications of FLT3 small molecule inhibitors have been investigated primarily in FLT3-ITD patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with the multikinase inhibitor sorafenib in addition to standard therapy. Here, we studied the sorafenib effect on proliferation in a panel of 13 FLT3-ITD and FLT3-ITD AML cell lines. Sorafenib IC50 values ranged from 0.001 to 5.6 μm, whereas FLT3-ITD cells (MOLM-13, MV4-11) were found to be more sensitive to sorafenib than FLT3-ITD cells. However, we identified two FLT3-ITD cell lines (MONO-MAC-1 and OCI-AML-2) which were also sorafenib sensitive. Phosphoproteome analyses revealed that the affected pathways differed in sorafenib sensitive FLT3-ITD and FLT3-ITD cells. In MV4-11 cells sorafenib suppressed mTOR signaling by direct inhibition of FLT3. In MONO-MAC-1 cells sorafenib inhibited the MEK/ERK pathway. These data suggest that the FLT3 status in AML patients might not be the only factor predicting response to treatment with sorafenib.

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