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.
Highlights
From the ‡Department of Medicine, Clinic III-Hematology/Oncology/ Palliative Care, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany; §Evotec (Munchen) GmbH, 82152 Martinsried, Germany; ¶Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany
We identified two cell lines (MONO-MAC-1 and OCI-acute myeloid leukemia (AML)-2) which were sensitive to sorafenib and negative for FLT3ITD or Fms like tyrosine kinase 3 (FLT3)-tyrosine kinase domain (TKD) gene mutations
There is a tendency that FLT3-ITDϩ AML cells are more sensitive than FLT3 wild-type cells, we could identify exceptions to this general trend
Summary
In acute myeloid leukemia (AML) the Fms like tyrosine kinase 3 (FLT3) gene is frequently altered by the insertion of internal tandem duplications (ITD) in the juxtamembrane domain or by point mutations in the tyrosine kinase domain (TKD). These genetic alterations lead to an aberrant activation of downstream signaling proteins and promote cell proliferation of AML cells [1]. Results of the randomized SORAML study showed a prolonged event-free survival in AML patients (Ͻ 60 years), who were treated with sorafenib in addition to standard induction and consolidation therapy [13]. Phosphoproteomics on Sorafenib Treated AML Cells esized, that the activation of other protein kinases beside FLT3 might predict the AML cell responsiveness to sorafenib
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