title: Activity of the novel mTOR inhibitor Torin-2 in B-precursor acute lymphoblastic leukemia and its therapeutic potential to prevent Akt reactivation.
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.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Simioni
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Cani
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: James
authors.initials: J
authors.lastname: McCubrey
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy. LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Luca M
authors.initials: LM
authors.lastname: Neri
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000068338:Everolimus; D006575:Heterocyclic Compounds, 3-Ring; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009287:Naphthyridines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; C548887:MK 2206; C546842:MTOR protein, human