Abstract
The PI3K/Akt/mTOR signaling cascade is a key regulatory pathway controlling cell growth and survival, and its dysregulation is a reported feature of B-precursor acute lymphoblastic leukemia (B-pre ALL). Torin-2 is a novel, second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. It has been shown that Torin-2 displayed dramatic antiproliferative activity across a panel of cancer cell lines. To investigate if Torin-2 could represent a new option for the treatment of B-pre ALL, we tested its activity on a panel of B-pre ALL cell lines. In all of them Torin-2 showed a powerful cytotoxic activity, inhibiting the growth of each cell line in a dose-dependent manner, with an IC₅₀ in the nanomolar range. Torin-2 caused both apoptosis and autophagy, induced cell cycle arrest in G₀/G₁ phase and affected both mTORC1 and mTORC2 activities as assessed by their specific substrate dephosphorylation. Torin-2 alone suppressed feedback activation of PI3K/Akt, whereas the mTORC1 inhibitor RAD001 required the addition of the Akt inhibitor MK-2206 to achieve the same effect. These pharmacological strategies targeting PI3K/Akt/mTOR at different points of the signaling pathway cascade might represent a new promising therapeutic strategy for treatment of B-pre ALL patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Autophagy / drug effects
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Cell Cycle Checkpoints / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Synergism
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Enzyme Activation / drug effects
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Everolimus
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / metabolism
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Naphthyridines / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism*
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Signal Transduction / drug effects
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Sirolimus / analogs & derivatives
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
Substances
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9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
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Heterocyclic Compounds, 3-Ring
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MK 2206
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Multiprotein Complexes
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Naphthyridines
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Protein Kinase Inhibitors
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Everolimus
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus