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PP2A-activating Drugs Enhance FLT3 Inhibitor Efficacy through AKT Inhibition-Dependent GSK-3β-Mediated c-Myc and

Mario Scarpa1,2, Prerna Singh1, Christopher M Bailey3,4

  • 1The University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center.

Molecular Cancer Therapeutics
|February 11, 2021
PubMed

Insights

PP2A-activating drugs enhance FLT3 inhibitor efficacy in acute myeloid leukemia (AML) by targeting FLT3-ITD signaling. This novel approach increases proteasomal degradation of c-Myc and Pim-1 oncogenes, improving treatment outcomes.

Area of Science:

  • Molecular Oncology
  • Cancer Therapeutics
  • Signal Transduction

Background:

  • Fms-like tyrosine-like kinase 3 internal tandem duplication (FLT3-ITD) is a key driver in 30% of acute myeloid leukemia (AML) cases, associated with poor prognosis.
  • Current FLT3 inhibitors show limited and transient efficacy, necessitating combination strategies targeting FLT3-ITD signaling pathways.
  • FLT3-ITD influences oncogenic Pim-1 kinase transcription and tumor suppressor protein phosphatase 2A (PP2A) activity, both regulating the c-Myc oncogene.

Purpose of the Study:

  • To investigate the mechanisms of action for combining FLT3 inhibitors with PP2A-activating drugs (PADs) in FLT3-ITD-positive AML.
  • To determine if PADs can enhance the therapeutic efficacy of FLT3 inhibitors by modulating key signaling molecules.

Main Methods:

  • Utilized FLT3-ITD-expressing cell lines and primary AML cells for in vitro studies.
  • Conducted in vivo studies using MV4-11 xenograft models.
  • Analyzed protein expression and degradation pathways, including AKT, GSK-3β, c-Myc, and Pim-1, using specific inhibitors and genetic modifications.

Main Results:

  • Cotreatment with PADs (FTY720, DT-061) and FLT3 inhibitors significantly enhanced growth suppression and apoptosis in FLT3-ITD AML cells in vitro and in vivo.
  • Combined treatment led to independent downregulation of c-Myc and Pim-1 via enhanced proteasomal degradation, preceded by AKT inactivation.
  • The mechanism involves AKT inactivation, subsequent GSK-3β activation, and phosphorylation-dependent proteasomal degradation of c-Myc (at T58) and Pim-1 (at S95/S4).

Conclusions:

  • PP2A-activating drugs potentiate FLT3 inhibitor efficacy in FLT3-ITD AML.
  • This synergistic effect is mediated by a novel pathway involving AKT inhibition, GSK-3β activation, and increased proteasomal degradation of c-Myc and Pim-1.
  • This combination strategy offers a promising therapeutic approach for FLT3-ITD-mutated AML.

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