Mammalian Target of Rapamycin as a Therapeutic Target in Leukemia
Francis J. Giles and Maher Albitar
Pages 653-661 (9)
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 cyclindependent 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.
mTOR, leukemia, phosphatidylinositol 3' kinase, AKT, CCI-779, RAD001, AP23573
Department of Leukemia,University of Texas, M.D. Anderson Cancer Center, 1515 HolcombeBoulevard, Box 428, Houston, Texas, 77030, USA.