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

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. 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. In acute myeloid leukemia (AML) 1The abbreviations used are: AML, acute myeloid leukemia; FLT3, Fms-like tyrosine kinase 3; ITD, internal tandem duplications; MSA, multistage activation; PEP, posterior error probability.1The abbreviations used are: AML, acute myeloid leukemia; FLT3, Fms-like tyrosine kinase 3; ITD, internal tandem duplications; MSA, multistage activation; PEP, posterior error probability. 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.Meshinchi S. Appelbaum F.R. Structural and functional alterations of FLT3 in acute myeloid leukemia.Clin. Cancer Res. 2009; 15: 4263-4269Crossref PubMed Scopus (169) Google Scholar). 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Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3.J Clin Oncol. 2010; 28: 4339-4345Crossref PubMed Scopus (403) Google Scholar), and quizartinib (AC220) (4.Cortes J.E. Kantarjian H. Foran J.M. Ghirdaladze D. Zodelava M. Borthakur G. Gammon G. Trone D. Armstrong R.C. James J. Levis M. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status.J Clin Oncol. 2013; 31: 3681-3687Crossref PubMed Scopus (285) Google Scholar) have been developed and evaluated either in clinical trials as monotherapy or in combination with standard chemotherapeutic protocols in the last years. 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A panel of 13 AML cell lines with different and FLT3 status used to study the effect of sorafenib cell lines were from and to the of cells were from and cells were for than lines were for and by In cell were for Kit of AML cell lines. the the and status and the cell growth in a and cell lines were Institute with and and MONO-MAC-1 cell in with and and cell lines were in with cell in with and cells were in with and and cell lines were in with and were in a from cell lines and for and of an by of the juxtamembrane domain from FLT3 to with a followed by mutations and were by of FLT3 followed by with and of as H. T. S. M. S. K. A. K. S. S. J. C. K. H. R. H. H. R. R. tandem duplication of FLT3 with in acute Scholar). Sorafenib from and were from inhibitors were in were with a of and were by with were in or and with of sorafenib, or for to cells were in a the of as the treated cells. cell were activity as C. M. S. M. F. S. D. A. G. S. O. M. 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M. of kinase inhibitor 2011; PubMed Scopus Google Scholar). also to such as and of on MONO-MAC-1 not the effect on cell of the tyrosine kinase activity of an effect be In inhibition of in MONO-MAC-1 with or the In FLT3 inhibition by on MV4-11 or MONO-MAC-1 cells as with sorafenib In the study that and FLT3 wild-type cell lines to treatment with sorafenib. the to be in wild-type cells. response in two of is by different of sorafenib mTOR signaling by FLT3 in the cell MEK/ERK signaling in the FLT3 sensitive cell Results of kinase inhibitor a that kinase be the of the inhibition of the MEK/ERK pathway. suggest that the FLT3 status in AML patients might not be the only for the treatment of patients with sorafenib. be in or in in are for and for for predicting response to treatment with sorafenib. data and the have been to the the with the data the for and to and for the with