The multi-targeted receptor tyrosine kinase inhibitor, Linifanib (ABT-869), induces apoptosis through an AKT and Glycogen Synthase Kinase 3β-dependent pathway

The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (15-35%) resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with acute myeloid leukemia (AML) harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not yet been characterized. Linifanib (ABT-869) is a multi-targeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this paper, we demonstrate that treatment with Linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo . We show that treatment with Linifanib reduces phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β). In addition, we show that inhibition of GSK3β decreases Linifanib-induced apoptosis. This study demonstrates the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations.