Mammalian Target of Rapamycin as a Therapeutic Target in Leukemia

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.

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…125 p70 S6K , which can also be directly activated by PDK1, phosphorylates the 40S ribosomal protein, S6, leading to active translation of mRNAs. 126 Figure 3 Interactions between Raf/MEK/ERK and PI3K/PTEN/Akt/ mTOR pathways in protein translational control. The Raf/MEK/Erk and PI3K/PTEN/Akt/mTOR pathways both serve to regulate the activity of mTORC1 a protein complex consisting of MLST8, raptor and most importantly mammalian target of rapamycin (mTOR).…”

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

“…134 p70S6K, which can also be directly activated by PDK-1, phosphorylates the 40s ribosomal protein, S6, leading to active translation of mRNAs. 135 By controlling protein synthesis, p70S6K and 4E-BP1 also regulate cell growth and hypertrophy, which are important processes for neoplastic progression. Therefore, even more distal steps in the PI3K/Akt pathway may have the potential to be exploited for cancer treatment.…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…Akt also acts to maintain cell survival through inhibition of BAD (Bcl2-antagonist of cell death). Furthermore, Akt promotes cell growth by phosphorylation of the downstream mTOR complex 1 (mTORC1) [45] , which translates mRNAs to protein via the p70S6K-S6 and 4E-BP1-eIF4E pathways [46] . In addition, hypoxia-inducible factor 1α (HIF-1α) was reported to be upregulated downstream of mTORC1, and therefore promotes angiogenesis by transcribing VEGF (vascular endothelial growth factor) [47] .…”