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AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells
E Griessinger1, V Imbert, P Lagadec
1INSERM, U526, Nice, France.
Abstract:
Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-kappaB) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-kappaB. Pharmacological inhibition of either FLT3 with AG1296 or NF-kappaB with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML.
Insights
Targeting the FLT3 pathway and nuclear factor kappaB (NF-kappaB) shows promise for treating acute myeloid leukemia (AML). Inhibition of these pathways induces cell death in AML cells, offering a potential new therapeutic strategy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation, resistance to apoptosis, and impaired differentiation.
- The nuclear factor kappaB (NF-kappaB) pathway is implicated in AML pathogenesis and drug resistance.
- Fms-like tyrosine kinase 3 (FLT3) mutations or overexpression are common in AML and drive proliferation.
Purpose of the Study:
- To investigate the interplay between FLT3 signaling and NF-kappaB activation in AML.
- To evaluate the therapeutic potential of inhibiting FLT3 and/or NF-kappaB in AML models.
Main Methods:
- Utilized Ba/F3 murine pre-B cells with FLT3 mutants (ITD, D835V, D835Y) and the MV4-11 human AML cell line.
- Assessed the effect of FLT3 stimulation on NF-kappaB activation.
- Administered pharmacological inhibitors of FLT3 (AG1296) and IkappaB kinase-2 (AS602868) targeting NF-kappaB.
Main Results:
- FLT3 stimulation, both normal and oncogenic, resulted in NF-kappaB activation.
- Inhibition of FLT3 or NF-kappaB reduced AML cell viability and induced cell death.
- The NF-kappaB inhibitor AS602868 directly inhibited FLT3 kinase activity.
Conclusions:
- FLT3 and NF-kappaB pathways are interconnected in AML.
- AS602868 demonstrates dual inhibitory activity against FLT3 and IKK2, crucial for AML.
- Targeting both FLT3 and NF-kappaB pathways with AS602868 presents a promising therapeutic strategy for AML.
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