FES kinases are required for oncogenic FLT3 signaling

Voisset, Edwige; Lopez, Sophie; Chaix, Amandine; Georges, Cédric; Hanssens, Katia; Prébet, Thomas; Dubreuil, Patrice; Sepulveda, Paulo De

doi:10.1038/leu.2009.301

Cited by 28 publications

(26 citation statements)

References 34 publications

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“…MV4-11, MOLM-13, MOLM-14 and THP-1 cells were treated with each inhibitor at a concentration of 1.0 μM, and apoptosis was assayed as Caspase 3/7 activity three days later. The three Fes inhibitors as well as tandutinib each induced significant apoptosis under these conditions in all three Flt3-ITD + AML cell lines but not in THP-1 cells, consistent with the observation that Fes is constitutively active in Flt3-ITD + AML cells [14] (Fig 3). Both TAE-684 and HG7-92-01 induced a percentage of apoptotic cells equal to or greater than that observed with tandutinib, while the effect of WZ4-49-1 was less pronounced.…”

Section: Resultssupporting

confidence: 87%

“…Furthermore, the activity of Flt3-ITD downstream signaling mediators, particularly STAT5 and PI3K, were also substantially decreased in Fes-knockdown cells. Co-immunoprecipitation studies demonstrated that the two kinases physically interact, and knockdown of Flt3-ITD led to a decrease in Fes kinase activity, supporting the idea that Fes is a downstream mediator of Flt3-ITD oncogenic signaling [14]. Finally, treatment of primary AML patient samples with the Flt3 inhibitor, SU5416, reduced both Flt3 and Fes activation.…”

Section: Introductionmentioning

confidence: 78%

“…Previous work by Voisset and colleagues has implicated Fes as an important downstream signaling partner for Flt3-ITD in AML [14]. They discovered that Fes was expressed and constitutively active in two Flt3-ITD + AML cell lines, MV4-11 and MOLM-14, as well as in primary AML bone marrow samples.…”

Section: Introductionmentioning

confidence: 99%

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Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth

Weir

Hellwig

et al. 2017

PLoS ONE

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Acute myelogenous leukemia (AML) is often associated with activating mutations in the receptor tyrosine kinase, Flt3, including internal tandem duplications (ITDs) within the regulatory juxtamembrane region. Previous studies have linked Flt3-ITD to the activation of the Fes protein tyrosine kinase in AML, and RNAi-knockdown studies suggest that Fes may be required for Flt3 function. In this study, we tested Fes inhibitors from three different chemical classes for their growth-suppressive activity against Flt3-ITD+ myeloid leukemia cell lines (MV4-11, MOLM-13 and MOLM-14) vs. myeloid cells with wild-type Flt3 (THP-1). All Fes inhibitors selectively inhibited the growth of Flt3-ITD+ AML cells, with IC50 values for diaminopyrimidine and pyrrolopyridine inhibitors ranging from 19 to 166 nM. In contrast, a pyrazolopyrimidine inhibitor was less potent in Flt3-ITD+ AML cells, with IC50 values in the 1.0 μM range. In vitro kinase assays showed that the most potent inhibitors of Flt3-ITD+ AML cell proliferation blocked both Fes and Flt3-ITD kinase activity, while the pyrazolopyrimidine was more selective for Fes vs. Flt3-ITD. All three inhibitors induced significant apoptosis in Flt3-ITD+ AML cells, with potency equivalent to or greater than the established Flt3-ITD inhibitor, tandutinib. Transformation of TF-1 cells with Flt3-ITD resulted in constitutive activation of endogenous Fes, and rendered the cells highly sensitive to all three Fes inhibitors with IC50 values in the 30–500 nM range. The pyrrolopyridine compound also induced apoptotic responses in patient-derived Flt3-ITD+ AML bone marrow cells but not in normal bone marrow mononuclear cells. These results demonstrate that Fes kinase activity contributes to Flt3-ITD signaling in AML, and suggests that dual inhibition of both Flt3 and Fes may provide a therapeutic advantage for the treatment of Flt3-ITD+ AML.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 78%

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Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth

Weir

Hellwig

et al. 2017

PLoS ONE

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“…However, the transient initial clinical response is followed by the appearance of resistant blasts. Recent efforts to identify alternative targets in FLT3-ITD AML lead to the identification of candidates such as PU.1 [21], NFATc1 [22], SIRT1 [23], PIM [24], FES [25], SYK [26], and BTK [27]. We describe here an essential pathway downstream of FLT3-ITD in AML cells.…”

Section: Discussionmentioning

confidence: 99%

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

et al. 2016

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CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.

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“…Indeed, to date, naturally occurring "gain-of-function" mutations have never been described. Nevertheless, in lymphoid type human cancers, hyper-activation of Fes kinase has proven to be crucial in sustaining the uncontrolled proliferation triggered by constitutively active mutants of membrane receptors, such as the inhibitor-resistant variant of c-Kit, KITD816V (expressed in several neoplasms) [49], and the FLT3 mutants expressed in acute myeloid leukaemia (AML) blasts or in AML cell lines [50].…”

Section: Fes In Cancer Biologymentioning

confidence: 99%

Role of the Non-Receptor Tyrosine Kinase Fes in Cancer

Condorelli¹,

Stec-Martyna²,

Zaborowska³

et al. 2011

CMC

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Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signaling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions.

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FES kinases are required for oncogenic FLT3 signaling

Cited by 28 publications

References 34 publications

Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth

Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth

An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

Role of the Non-Receptor Tyrosine Kinase Fes in Cancer

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