Mammalian target of rapamycin as a therapeutic target in leukemia

Francis J. Giles*, Maher Albitar

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

58 Scopus citations

Abstract

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)653-661
Number of pages9
JournalCurrent Molecular Medicine
Volume5
Issue number7
DOIs
StatePublished - Nov 2005

Keywords

  • AKT
  • AP23573
  • CCl-779
  • Leukemia
  • Phosphatidylinositol 3′ kinase
  • RAD001
  • mTOR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology

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