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Review
. 2010 Jun;1(2):89-103.
doi: 10.18632/oncotarget.114.

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients

Alberto M Martelli  1 , Camilla Evangelisti, Francesca Chiarini, James A McCubrey
Affiliations
Review

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients

Alberto M Martelli et al. Oncotarget. 2010 Jun.

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.

Keywords: PI3K/Akt/mTOR; combination therapy; leukemia; leukemic stem cells; signal transduction modulators; targeted therapy.

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Conflict of interest statement

The authors have no conflict of interests to declare.

Figures

Fig. 1.
Fig. 1.
The PI3K/Akt/mTOR signaling pathway. GPCRs, RTKs, and Ras activate PI3K. PI3K generates PtdIns (3,4,5)P3 from PtdIns (4,5)P2. PtdIns (3,4,5)P3 attracts to the plasma membrane PDK1 which phosphorylates Akt on Thr308. Full Akt activation requires Ser473 phosphorylation which is effected by mTORC2. Most of the Akt substrates are inactivated by phosphorylation. Active Akt inhibits TSC2 activity through direct phosphorylation. TSC2 is a GAP that functions in association with TSC1 to inactivate the small G protein Rheb. Akt-driven TSC1/TSC2 complex inactivation allows Rheb to accumulate in a GTP-bound state. Rheb-GTP then activates the protein kinase activity of mTORC1. mTORC1 targets p70S6K and 4E-BP1 which are critical for translation. 4E-BP1 phosphorylation by mTORC1 results in the release of eIF4E, while p70S6K phosphorylates ribosomal S6 protein. The TSC1/2 complex is required to activate also mTORC2. However, other signaling cascades impinge on mTORC1, including GSK3β, the Ras/Raf/MEK/ERK1/2/p90RSK pathway, and the LKB1/AMPK network which is sensitive to the ADP/ATP ratio. Arrows indicate activating events, whereas perpendicular lines indicate inhibitory events.
Fig. 2.
Fig. 2.
A schematic presentation of mTOR structure. Some of the proteins interacting with mTOR domains are highlighted. The FRB domain is where the FKBP12 and rapamycin complex binds which is within the region that binds FKBP38.
Fig. 3.
Fig. 3.
Constitutive activation of PI3K/Akt signaling in AML cells. In this cartoon, mutated (Mut) C-Kit, FLT3, or Ras, and autocrine/paracrine secretion of growth factors (VEGF, IGF-1) impinge upon increased levels of p110β and/or p110δ PI3K. This results in high levels of PtdIns (3,4,5)P3 synthesized at the plasma membrane from PtdIns (4,5)P2. PtdIns (3,4,5)P3 recruits at the plasma membrane both PDK1 and inactive Akt (Akt off). PDK1 phoshorylates Akt on Thr308, whereas phosphorylation on Ser473 is driven by mTORC2. These two phosphorylative events fully activates Akt (Akt on). Bone marrow stromal cells secrete CXCL12 and fibronectin. Fibronectin, by interacting with β integrins, could activate ILK which, in turn, stimulates mTORC2 activity on Ser473 Akt. CXCL12 binds its receptor CXCR4, a GPCR which results in increased PI3K activity. Bone marrow stromal cells could also secrete VEGF and IGF-1. Activated Akt migrates to both nucleus and cytosol to phosphorylate its substrates.
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