681
Views
91
CrossRef citations to date
0
Altmetric
Reviews

Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

, MD PhD, , PhD, , BSc, , BSc, , MD PhD & , PhD
Pages 1333-1349 | Published online: 14 Aug 2009

Bibliography

  • Smith M, Barnett M, Bassan R, et al. Adult acute myeloid leukaemia. Crit Rev Oncol Hematol 2004;50:197-222
  • Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood 2005;106:1154-63
  • Ravandi F, Burnett AK, Agura ED, Kantarjian HM. Progress in the treatment of acute myeloid leukemia. Cancer 2007;110:1900-10
  • Petrie K, Zelent A, Waxman S. Differentiation therapy of acute myeloid leukemia: past, present and future. Curr Opin Hematol 2009;16:84-91
  • Stapnes C, Gjertsen BT, Reikvam H, Bruserud O. Targeted therapy in acute myeloid leukaemia: current status and future directions. Expert Opin Investig Drugs 2009;18:433-55
  • Mayani H, Flores-Figueroa E, Chavez-Gonzalez A. In vitro biology of human myeloid leukemia. Leuk Res 2009;33:624-37
  • Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645-8
  • Misaghian N, Ligresti G, Steelman LS, et al. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 2009;23:25-42
  • McCubrey JA, Abrams SL, Ligresti G, et al. Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia 2008;22:2080-90
  • Steelman LS, Abrams SL, Whelan J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008;22:686-707
  • Scholl C, Gilliland DG, Frohling S. Deregulation of signaling pathways in acute myeloid leukemia. Semin Oncol 2008;35:336-45
  • Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008;27:5497-510
  • Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005;94:29-86
  • LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008;11:32-50
  • Martelli AM, Tazzari PL, Evangelisti C, et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem 2007;14:2009-23
  • Horn S, Bergholz U, Jucker M, et al. Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells. Oncogene 2008;27:4096-106
  • Brazil DP, Yang ZZ, Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 2004;29:233-42
  • Franke TF. PI3K/Akt: getting it right matters. Oncogene 2008;27:6473-88
  • Jia S, Roberts TM, Zhao JJ. Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 2009;21:199-208
  • Fruman DA, Bismuth G. Fine tuning the immune response with PI3K. Immunol Rev 2009;228:253-72
  • Kok K, Geering B, Vanhaesebroeck B. Regulation of phosphoinositide 3-kinase expression in health and disease. Trends Biochem Sci 2009;34:115-27
  • Backer JM. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 2008;410:1-17
  • Ligresti G, Militello L, Steelman LS, et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle 2009;8:1352-8
  • Denley A, Kang S, Karst U, Vogt PK. Oncogenic signaling of class I PI3K isoforms. Oncogene 2008;27:2561-74
  • Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008;27:5486-96
  • Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 2003;278:49530-6
  • Arboleda MJ, Lyons JF, Kabbinavar FF, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of β1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 2003;63:196-206
  • Bozulic L, Hemmings BA. PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol 2009;21:256-61
  • Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-74
  • Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 2004;15:177-82
  • Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-44
  • Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 2009;21:656-64
  • Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signal 2009;21:827-35
  • Rosner M, Hengstschlager M. Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum Mol Genet 2008;17:2934-48
  • Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84
  • Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene 2006;25:6416-22
  • Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715-24
  • Crazzolara R, Cisterne A, Thien M, et al. Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood 2009;113:3297-306
  • Mavrakis KJ, Zhu H, Silva RL, et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 2008;22:2178-88
  • Ma L, Chen Z, Erdjument-Bromage H, et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005;121:179-93
  • Hong SP, Leiper FC, Woods A, et al. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 2003;100:8839-43
  • Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37:217-22
  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-101
  • Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:1122-8
  • Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004;14:1650-6
  • Bhaskar PT, Hay N. The two TORCs and Akt. Dev Cell 2007;12:487-502
  • Shi Y, Yan H, Frost P, et al. Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 2005;4:1533-40
  • Breuleux M, Klopfenstein M, Stephan C, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 2009;8:742-53
  • Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008;118:3065-74
  • O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8
  • Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 2008;27:5477-85
  • Stiles BL. Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. Int J Biochem Cell Biol 2009;41:757-61
  • Gutierrez A, Sanda T, Grebliunaite R, et al. High frequency of PTEN, PI3K and AKT abnormalities in T cell acute lymphoblastic leukemia. Blood 2009: published on line 20 May 2009, doi 10.1182/blood-2009-02-206722
  • Kalesnikoff J, Sly LM, Hughes MR, et al. The role of SHIP in cytokine-induced signaling. Rev Physiol Biochem Pharmacol 2003;149:87-103
  • Ong CJ, Ming-Lum A, Nodwell M, et al. Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 2007;110:1942-9
  • Hazen AL, Smith MJ, Desponts C, et al. SHIP is required for a functional hematopoietic stem cell niche. Blood 2009;113:2924-33
  • Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 2009;1795:1-15
  • Brognard J, Newton AC. PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab 2008;19:223-30
  • Xu Q, Simpson SE, Scialla TJ, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003;102:972-80
  • Min YH, Eom JI, Cheong JW, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 2003;17:995-7
  • Brandts CH, Sargin B, Rode M, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005;65:9643-50
  • Grandage VL, Gale RE, Linch DC, Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-κB, Mapkinase and p53 pathways. Leukemia 2005;19:586-94
  • Gallay N, Dos Santos C, Cuzin L, et al. The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia. Leukemia 2009;23:1029-38
  • Muranyi AL, Dedhar S, Hogge DE. Combined inhibition of integrin linked kinase and FMS-like tyrosine kinase 3 is cytotoxic to acute myeloid leukemia progenitor cells. Exp Hematol 2009;37:450-60
  • Min YH, Cheong JW, Kim JY, et al. Cytoplasmic mislocalization of p27Kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase B and poor prognosis in acute myelogenous leukemia. Cancer Res 2004;64:5225-31
  • Kornblau SM, Womble M, Qiu YH, et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 2006;108:2358-65
  • Tamburini J, Elie C, Bardet V, et al. Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. Blood 2007;110:1025-8
  • Kornblau SM, Tibes R, Qiu YH, et al. Functional proteomic profiling of AML predicts response and survival. Blood 2009;113:154-64
  • Tazzari PL, Cappellini A, Ricci F, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 2007;21:427-38
  • Schaich M, Soucek S, Thiede C, et al. MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 2005;128:324-32
  • Faderl S, Pal A, Bornmann W, et al. Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells. Cancer Res 2009;69:3910-7
  • Birkenkamp KU, Geugien M, Schepers H, et al. Constitutive NF-κB DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB-dependent pathway. Leukemia 2004;18:103-12
  • Sujobert P, Bardet V, Cornillet-Lefebvre P, et al. Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 2005;106:1063-6
  • Billottet C, Grandage VL, Gale RE, et al. A selective inhibitor of the p110δ isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 2006;25:6648-59
  • Doepfner KT, Spertini O, Arcaro A. Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia 2007;21:1921-30
  • Imai N, Miwa H, Shikami M, et al. Growth inhibition of AML cells with specific chromosome abnormalities by monoclonal antibodies to receptors for vascular endothelial growth factor. Leuk Res 2009: published online 31 March 2009, doi:10.1016/j.leukres.2009.03.006
  • Bohm A, Aichberger KJ, Mayerhofer M, et al. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells. Eur J Clin Invest 2009;39:395-405
  • Tazzari PL, Tabellini G, Bortul R, et al. The insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 induces apoptosis in acute myeloid leukemia cells exhibiting autocrine insulin-like growth factor-I secretion. Leukemia 2007;21:886-96
  • Pearn L, Fisher J, Burnett AK, Darley RL. The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 2007;109:4461-9
  • Fierro FA, Brenner S, Oelschlaegel U, et al. Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia. Leukemia 2009;23:393-6
  • Fiegl M, Samudio I, Clise-Dwyer K, et al. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood 2009;113:1504-12
  • Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009;113:6215-24
  • Matsunaga T, Takemoto N, Sato T, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003;9:1158-65
  • Matsunaga T, Fukai F, Miura S, et al. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia 2008;22:353-60
  • Tabe Y, Jin L, Tsutsumi-Ishii Y, et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007;67:684-94
  • McDonald PC, Oloumi A, Mills J, et al. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival. Cancer Res 2008;68:1618-24
  • Bousquet M, Recher C, Queleen C, et al. Assessment of somatic mutations in phosphatidylinositol 3-kinase gene in human lymphoma and acute leukaemia. Br J Haematol 2005;131:411-3
  • Tibes R, Kornblau SM, Qiu Y, et al. PI3K/AKT pathway activation in acute myeloid leukaemias is not associated with AKT1 pleckstrin homology domain mutation. Br J Haematol 2008;140:344-7
  • Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 2000;20:5010-8
  • Cheong JW, Eom JI, Maeng HY, et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003;122:454-6
  • Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006;441:475-82
  • Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006;441:518-22
  • Tamburini J, Chapuis N, Bardet V. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood 2008;111:379-82
  • Chow S, Minden MD, Hedley DW. Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients. Exp Hematol 2006;34:1183-91
  • Dos Santos C, Demur C, Bardet V, et al. A critical role for Lyn in acute myeloid leukemia. Blood 2008;111:2269-79
  • Green AS, Tamburini J, Willems L, et al. mTORC1 activity is independent of PI3K/Akt but controlled by AMPK in acute myeloid leukemia [abstract]. Blood 2008;112:935
  • Xu Z, Wang M, Wang L, et al. Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leuk Res 2009;33:891-7
  • Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood 2005;106:4261-8
  • Vanhaesebroeck B, Leevers SJ, Ahmadi K, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001;70:535-602
  • Bozulic L, Surucu B, Hynx D, Hemmings BA. PKBα/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 2008;30:203-13
  • Zhao S, Konopleva M, Cabreira-Hansen M, et al. Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. Leukemia 2004;18:267-75
  • Neri LM, Borgatti P, Tazzari PL, et al. The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res 2003;1:234-46
  • Yu K, Lucas J, Zhu T, et al. PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors. Cancer Biol Ther 2005;4:538-45
  • Ihle NT, Paine-Murrieta G, Berggren MI, et al. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 2005;4:1349-57
  • Garlich JR, De P, Dey N, et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 2008;68:206-15
  • Ihle NT, Powis G. Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 2009;8:1-9
  • Billottet C, Banerjee L, Vanhaesebroeck B, Khwaja A. Inhibition of class I phosphoinositide 3-kinase activity impairs proliferation and triggers apoptosis in acute promyelocytic leukemia without affecting atra-induced differentiation. Cancer Res 2009;69:1027-36
  • Foukas LC, Claret M, Pearce W, et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 2006;441:366-70
  • Knight ZA, Gonzalez B, Feldman ME, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-47
  • Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008;27:5511-26
  • Chun KH, Kosmeder JW 2nd, Sun S, et al. Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 2003;95:291-302
  • Bortul R, Tazzari PL, Billi AM, et al. Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway. Br J Haematol 2005;129:677-86
  • Bayascas JR. Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle 2008;7:2978-82
  • Peifer C, Alessi DR. Small-molecule inhibitors of PDK1. Chem Med Chem 2008;3:1810-38
  • Hahn M, Li W, Yu C, et al. Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 2005;4:457-70
  • Sampath D, Cortes J, Estrov Z, et al. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 2006;107:2517-24
  • Zhu J, Huang JW, Tseng PH, et al. From the cyclooxygenase-2 inhibitor celecoxib to a novel class of 3-phosphoinositide-dependent protein kinase-1 inhibitors. Cancer Res 2004;64:4309-18
  • Casanova I, Bosch R, Lasa A, et al. A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cells. Int J Cancer 2008;123:217-26
  • Stauffer F, Maira SM, Furet P, Garcia-Echeverria C. Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. Bioorg Med Chem Lett 2008;18:1027-30
  • Weisberg E, Banerji L, Wright RD, et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells. Blood 2008;111:3723-34
  • van Blitterswijk WJ, Verheij M. Anticancer alkylphospholipids: mechanisms of action, cellular sensitivity and resistance, and clinical prospects. Curr Pharm Des 2008;14:2061-74
  • Catley L, Hideshima T, Chauhan D, et al. Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol 2007;35:1038-46
  • Papa V, Tazzari PL, Chiarini F, et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008;22:147-60
  • Rahmani M, Reese E, Dai Y, et al. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Res 2005;65:2422-32
  • Tazzari PL, Tabellini G, Ricci F, et al. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res 2008;68:9394-403
  • Chiarini F, Del Sole M, Mongiorgi S, et al. The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia 2008;22:1106-16
  • Meuillet EJ, Mahadevan D, Vankayalapati H, et al. Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues. Mol Cancer Ther 2003;2:389-99
  • Gills JJ, Holbeck S, Hollingshead M, et al. Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol Cancer Ther 2006;5:713-22
  • Martelli AM, Tazzari PL, Tabellini G, et al. A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. Leukemia 2003;17:1794-805
  • Tabellini G, Tazzari PL, Bortul R, et al. Novel 2′-substituted, 3′-deoxy-phosphatidyl-myo-inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3-kinase/Akt pathway. Br J Haematol 2004;126:574-82
  • Gills JJ, Castillo SS, Zhang C, et al. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38α, through MKK3/6-independent and -dependent mechanisms. J Biol Chem 2007;282:27020-9
  • Memmott RM, Gills JJ, Hollingshead M, et al. Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinase-dependent death in LKB1-mutant non small cell lung cancer cells. Cancer Res 2008;68:580-8
  • Barnett SF, Defeo-Jones D, Fu S, et al. Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem J 2005;385:399-408
  • Yang L, Dan HC, Sun M, et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 2004;64:4394-9
  • Ravandi F, Sampath D, Plunkett W, et al. Phase I study of the Akt-Inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancy [abstract]. Blood 2008;112:2987
  • Rhodes N, Heerding DA, Duckett DR, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008;68:2366-74
  • Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009;113:1723-9
  • Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs 2008;17:1717-34
  • Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon α, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81
  • Le Tourneau C, Faivre S, Serova M, Raymond E. mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer 2008;99:1197-203
  • Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006;12:122-7
  • Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol 2009;145:569-80
  • Dal Col J, Zancai P, Terrin L, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 2008;111:5142-51
  • Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007;13:3109-14
  • Leone M, Crowell KJ, Chen J, et al. The FRB domain of mTOR: NMR solution structure and inhibitor design. Biochemistry 2006;45:10294-302
  • Foster DA, Toschi A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 2009;8:1026-9
  • Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007;109:3509-12
  • Recher C, Beyne-Rauzy O, Demur C, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005;105:2527-34
  • Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene 2006;25:6436-46
  • Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006;12:5165-73
  • Rizzieri DA, Feldman E, Dipersio JF, et al. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008;14:2756-62
  • Karp JE, Flatten K, Feldman EJ, et al. Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. Blood 2009;113:4841-52
  • Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38
  • Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009;284:8023-32
  • Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341-9
  • Raynaud FI, Eccles S, Clarke PA, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 2007;67:5840-50
  • Chiarini F, Fala F, Tazzari PL, et al. Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 2009;69:3520-8
  • Kojima K, Shimanuki M, Shikami M, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 2008;22:1728-36
  • Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 2008;22:1698-706
  • Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008;7:1851-63
  • Gora-Tybor J, Robak T. Targeted drugs in chronic myeloid leukemia. Curr Med Chem 2008;15:3036-51
  • Hambley TW, Hait WN. Is anticancer drug development heading in the right direction? Cancer Res 2009;69:1259-62
  • Weinstein IB, Joe A. Oncogene addiction. Cancer Res 2008;68:3077-80
  • Eyler CE, Foo WC, LaFiura KM, et al. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 2008;26:3027-36
  • Guertin DA, Stevens DM, Saitoh M, et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 2009;15:148-59
  • Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 2009;106:268-73
  • Gallia GL, Tyler BM, Hann CL, et al. Inhibition of Akt inhibits growth of glioblastoma and glioblastoma stem-like cells. Mol Cancer Ther 2009;8:386-93
  • Bleau AM, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 2009;4:226-35
  • Zunder ER, Knight ZA, Houseman BT, et al. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 α. Cancer Cell 2008;14:180-92
  • Buitenhuis M, Coffer PJ. The role of the PI3K-PKB signaling module in regulation of hematopoiesis. Cell Cycle 2009;8:560-6
  • Campone M, Levy V, Bourbouloux E, et al. Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours. Br J Cancer 2009;100:315-21
  • Amato RJ, Jac J, Giessinger S, et al. A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 2009: published online Mar 20, doi: 10.1002/cncr.24280
  • Volpe G, Panuzzo C, Ulisciani S, Cilloni D. Imatinib resistance in CML. Cancer Lett 2009;274:1-9
  • Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006;20:911-28
  • Yap TA, Garrett MD, Walton MI, et al. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmcol 2008;8:393-412
  • Tazzari PL, Cappellini A, Grafone T, et al. Detection of serine 473 phosphorylated Akt in acute myeloid leukaemia blasts by flow cytometry. Br J Haematol 2004;126:675-81
  • Bardet V, Tamburini J, Ifrah N, et al. Single cell analysis of phosphoinositide 3-kinase/Akt and ERK activation in acute myeloid leukemia by flow cytometry. Haematologica 2006;91:757-64

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.