The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cell by chemotherapeutic agents
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en augmentant l'activité de p53, le dasatinib renforce l'efficacité de la daunorubicine dans le traitement des patients atteints d'une leucémie myéloïde aiguë
The SRC Family Kinases (SFKs) and the receptor tyrosine kinase c-Kit, are activated in human acute myeloid leukemia (AML) cells. We show here that the SFKs LYN, HCK or FGR are overexpressed and activated in AML progenitor cells. Treatment with the SFK and c-KIT inhibitor dasatinib selectively inhibits human AML stem/progenitor cell growth in vitro. Importantly, dasatinib markedly increases the elimination of AML stem cells capable of engrafting immunodeficient mice by chemotherapeutic agents. In vivo dasatinib treatment enhances chemotherapy induced targeting of primary murine AML stem cells capable of regenerating leukemia in secondary recipients. Our studies suggest that enhanced targeting of AML cells by the combination of dasatinib with daunorubicin (DNR) may be related to inhibition of AKT mediated HDM2 phosphorylation, resulting in enhanced p53 activity in AML cells. Combined treatment using dasatinib and chemotherapy provides a novel approach to increase p53 activity and enhance targeting of AML stem cells.