title: The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway.
abstract: 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 (AML; 15%-35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with 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 been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show 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 shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations.
authors.affiliation: Division of Hematology-Oncology, Gwynne Hazen Cherry Memorial Laboratories, Mattel Children's Hospital UCLA, Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Hernandez-Davies
authors.forename: Joan P
authors.initials: JP
authors.lastname: Zape
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Landaw
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tan
authors.forename: Ajia
authors.initials: A
authors.lastname: Presnell
authors.forename: Diana
authors.initials: D
authors.lastname: Griffith
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D007377:Interleukin-3 / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D009154:Mutation; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D007191:Indazoles; D007377:Interleukin-3; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C513486:linifanib; D051941:fms-Like Tyrosine Kinase 3; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride