title: Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential.
abstract: B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: L M
authors.initials: LM
authors.lastname: Neri
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cani
authors.affiliation: 1] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy [2] Institute of Molecular Genetics, National Research Council, Pavia, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Simioni
authors.affiliation: University of Rostock, Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, Rostock, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Junghanss
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ricci
authors.affiliation: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: P L
authors.initials: PL
authors.lastname: Tazzari
authors.affiliation: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pagliaro
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Capitani
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; D000068338:Everolimus; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C528328:GSK690693; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D046912:Multiprotein Complexes; D010069:Oxadiazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C401859:temsirolimus; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references.citation: Blood Rev. 2012 May;26(3):123-35
references.pmid: 22436535
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15113-8
references.pmid: 14657335
references.citation: Mol Cancer. 2012 Nov 20;11:85
references.pmid: 23167739
references.citation: Leukemia. 2011 Jun;25(6):960-7
references.pmid: 21455214
references.citation: Hum Pathol. 2012 Sep;43(9):1347-62
references.pmid: 22575265
references.citation: Blood. 2005 Aug 15;106(4):1400-6
references.pmid: 15878982
references.citation: Curr Biol. 2013 Jan 7;23(1):R33-45
references.pmid: 23305670
references.citation: Cancer Lett. 2012 Dec 28;325(2):139-46
references.pmid: 22781393
references.citation: Anticancer Agents Med Chem. 2010 Sep;10(7):571-81
references.pmid: 20812900
references.citation: Cancer Res. 2012 Sep 1;72(17):4483-93
references.pmid: 22815528
references.citation: J Biol Chem. 1999 Apr 2;274(14):9463-71
references.pmid: 10092628
references.citation: Oncotarget. 2012 Apr;3(4):371-94
references.pmid: 22564882
references.citation: Blood. 2009 Feb 19;113(8):1723-9
references.pmid: 19064730
references.citation: Mol Cancer Ther. 2010 Jul;9(7):1956-67
references.pmid: 20571069
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):6029-39
references.pmid: 21169255
references.citation: Int J Cancer. 2013 Nov;133(9):2065-76
references.pmid: 23588885
references.citation: Biochem J. 2011 Apr 15;435(2):539-44
references.pmid: 21348862
references.citation: Curr Opin Genet Dev. 2006 Feb;16(1):78-84
references.pmid: 16359855
references.citation: Ann Oncol. 2005 Apr;16(4):525-37
references.pmid: 15728109
references.citation: Cell Death Differ. 2009 Jan;16(1):1-2
references.pmid: 19079285
references.citation: Cancer Res. 2000 Aug 15;60(16):4320-3
references.pmid: 10969768
references.citation: Haematologica. 2011 Jan;96(1):69-77
references.pmid: 20952516
references.citation: Blood. 2010 Dec 23;116(26):5983-90
references.pmid: 20889920
references.citation: Leukemia. 2013 Jul;27(7):1479-86
references.pmid: 23321953
references.citation: Leukemia. 1996 Oct;10(10):1576-83
references.pmid: 8847892
references.citation: Leukemia. 2013 Mar;27(3):650-60
references.pmid: 23038273
references.citation: BMC Cancer. 2010 Oct 15;10:560
references.pmid: 20950443
references.citation: Leukemia. 2012 Feb;26(2):271-9
references.pmid: 21844871
references.citation: Clin Cancer Res. 2006 Sep 1;12(17):5165-73
references.pmid: 16951235
references.citation: Leukemia. 2012 Jun;26(6):1195-202
references.pmid: 22143671
references.citation: Immunol Res. 2008;42(1-3):84-105
references.pmid: 18716718
references.citation: J Cell Physiol. 2011 Mar;226(3):822-31
references.pmid: 20857426
references.citation: Leukemia. 2011 Jul;25(7):1064-79
references.pmid: 21436840
references.citation: Leukemia. 2011 Feb;25(2):313-20
references.pmid: 21109770
references.citation: Leukemia. 2011 Dec;25(12):1857-68
references.pmid: 21926961
references.citation: Cancer. 2011 Aug 15;117(16):3763-73
references.pmid: 21387259
references.citation: Blood. 2007 Apr 15;109(8):3509-12
references.pmid: 17179228
references.citation: Leukemia. 2008 Dec;22(12):2159-68
references.pmid: 18784743
references.citation: Cancer Cell. 2006 Feb;9(2):77-9
references.pmid: 16473275
references.citation: Leukemia. 2010 Oct;24(10):1686-99
references.pmid: 20703258
references.citation: Med Oncol. 2010 Jun;27(2):255-61
references.pmid: 19301157
references.citation: Leukemia. 2011 May;25(5):781-91
references.pmid: 21331075
references.citation: Leukemia. 2012 Nov;26(11):2336-42
references.pmid: 22614243
references.citation: Cell Death Differ. 2000 Dec;7(12):1263-9
references.pmid: 11175264
references.citation: Leukemia. 2011 Feb;25(2):341-7
references.pmid: 21135857
references.citation: Ann Surg Oncol. 2010 Sep;17(9):2486-93
references.pmid: 20339946
references.citation: Blood. 2006 Oct 1;108(7):2358-65
references.pmid: 16763210
references.citation: Autophagy. 2009 Jul;5(5):727-8
references.pmid: 19363300
references.citation: Pediatr Blood Cancer. 2012 Jul 15;59(1):83-9
references.pmid: 22183914
references.citation: J Biol Chem. 2012 Apr 6;287(15):11677-88
references.pmid: 22351764
references.citation: Leukemia. 2013 Feb;27(2):325-35
references.pmid: 22902361
references.citation: Leukemia. 2012 May;26(5):927-33
references.pmid: 22094587
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Cancer Genet Cytogenet. 2010 Jul 1;200(1):8-15
references.pmid: 20513528
references.citation: Acta Pharmacol Sin. 2008 Apr;29(4):481-8
references.pmid: 18358095
references.citation: Leukemia. 2003 Mar;17(3):590-603
references.pmid: 12646949
references.citation: Leukemia. 2012 Jan;26(1):91-100
references.pmid: 21968881
references.citation: PLoS One. 2012;7(2):e31331
references.pmid: 22355357