The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway.

Jenny E. Hernandez-Davies, Joan P. Zape, Elliot M. Landaw, Xiaolin Tan, Ajia Presnell, Diana Griffith, Michael Heinrich, Keith B. Glaser, Kathleen M. Sakamoto

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)949-959
    Number of pages11
    JournalMolecular Cancer Therapeutics
    Volume10
    Issue number6
    DOIs
    StatePublished - Jun 2011

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    N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N1-(2-fluoro-5-methylphenyl)urea
    Glycogen Synthase Kinase 3
    Receptor Protein-Tyrosine Kinases
    Apoptosis
    Mutation
    Cell Proliferation
    Therapeutics

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway. / Hernandez-Davies, Jenny E.; Zape, Joan P.; Landaw, Elliot M.; Tan, Xiaolin; Presnell, Ajia; Griffith, Diana; Heinrich, Michael; Glaser, Keith B.; Sakamoto, Kathleen M.

    In: Molecular Cancer Therapeutics, Vol. 10, No. 6, 06.2011, p. 949-959.

    Research output: Contribution to journalArticle

    Hernandez-Davies, Jenny E. ; Zape, Joan P. ; Landaw, Elliot M. ; Tan, Xiaolin ; Presnell, Ajia ; Griffith, Diana ; Heinrich, Michael ; Glaser, Keith B. ; Sakamoto, Kathleen M. / The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 6. pp. 949-959.
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    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.",
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