Évaluation préclinique du potentiel thérapeutique d'un inhibiteur de IKK2 et de FLT3 dans le traitement des leucémies aiguës myéloïdes

Fms Like Tyrosine Kinase 3 (FLT3) is the most frequently mutated gene in LAM. Its mutations lead to a constitutive activation of FLT3 which constitute a proliferation and survival advantage for leukemic cells. Using cell lines carrying wild type or mutated forms of FLT3, we have shown that both physiological and oncological activation of FLT3 lead to the NF-kB pathway activation. Surprisingly, we have discovered during this study that the IKK2 inhibitor AS602868 directly interferes with the FLT3 kinase activity. This discovery encourages the therapeutic testing of AS602868, as it is targeting two kinases that play major roles for the pathogenesis of AML. To evaluate the therapeutic potential of AS602868, we have compared its effect on different steps of both the hematopoietic and leukemic process, in different types of experiments. In vitre and in vivo experiments have all demonstrated the existence of a pharmacological targeting of the stem-progenitor leukemic population by AS602868. The identical treatment in the control conditions had no or very few side effects on the normal haematopoiesis. We show for the first time the preferential targeting of the LSCs in vivo with an IKK2 inhibitor. Our results show that both normal and oncogenic activation of FLT3 can lead to the abnormal constitutive activation of the NF-kB pathway, present in AML. Our study identifies a new target of the IKK2 inhibitor AS602868 and reinforces the perspects of its use in the clinic. Finally, this work suggests that the pharmacological targeting of the leukemic stem cells in vivo has to be the main objective of the new therapies of AML.