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Mol Cell Proteomics. 2017 Jul;16(7):1365-1376. doi: 10.1074/mcp.M117.067462. Epub 2017 Apr 27.

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

Author information

1
From the ‡Department of Medicine, Clinic III-Hematology/Oncology/Palliative Care, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany.
2
§Evotec (München) GmbH, 82152 Martinsried, Germany.
3
§Evotec (München) GmbH, 82152 Martinsried, Germany; christoph.schaab@evotec.com.
4
¶Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany.

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.

PMID:
28450419
PMCID:
PMC5500767
DOI:
10.1074/mcp.M117.067462
[Indexed for MEDLINE]
Free PMC Article

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