Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia

Haematologica

Volumn 95, Issue 5, 2010, Pages 819-828

  Park, Sophie ^a,b,c,d,f   Chapuis, Nicolas ^a,b,c,d   Tamburini, Jérôme ^a,b,c,d,f   Bardet, Valérie ^a,b,c,d   Cornillet Lefebvre, Pascale ^e,f   Willems, Lise ^a,b,c   Green, Alexa ^a,b,c   Mayeux, Patrick ^a,b,c   Lacombe, Catherine ^a,b,c,d,f   Bouscary, Didier ^a,b,c,d,f  

^a CNRS   (France)

^b INSERM   (France)

^c UNIVERSITÉ PARIS DESCARTES   (France)

^d Hôpital Cochin ^*  (France)

^e REIMS UNIVERSITY HOSPITAL   (France)

^f Groupe Ouest Est des Leucemies et Autres Maladies du Sang GOELAMS   (France)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (6 AMINO 9 PURINYLMETHYL) 5 METHYL 3 (2 METHYLPHENYL) 3H QUINAZOLIN 4 ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 7 HYDROXYSTAUROSPORINE; ACETYLCYSTEINE; AETERNA; AEZS 127; ANTINEOPLASTIC AGENT; AQUINOX; AQX MN100; AVE 1642; CAL 101; DEGUELIN; EVEROLIMUS; KP 372 1; KRX 0601; MAMMALIAN TARGET OF RAPAMYCIN; NVP AEW 541; PERIFOSINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN SHIP1; RAPAMYCIN; SOMATOMEDIN C; SOMATOMEDIN C RECEPTOR; TANESPIMYCIN; TEMSIROLIMUS; TRICIBINE; TRICIRIBINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VIOQUEST; WORTMANNIN; XL 765;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIOXIDANT ACTIVITY; ARTICLE; AUTOCRINE EFFECT; CANCER INCIDENCE; CLINICAL TRIAL; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG SCREENING; DRUG TARGETING; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; HEMATOPOIESIS; HUMAN; LEUKEMOGENESIS; NONHUMAN; PARACRINE SIGNALING; PROGNOSIS; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; HUMANS; LEUKEMIA, MYELOID, ACUTE; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 77952299648     PISSN: 03906078     EISSN: 15928721     Source Type: Journal    
DOI: 10.3324/haematol.2009.013797     Document Type: Article

References (115)

1. Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H. The molecular pathogenesis of acute myeloid leukemia. Crit Rev Oncol Hematol. 2005;56(2):195-221.
2. Rowe JM. Why is clinical progress in acute myelogenous leukemia so slow? Best Pract Res Clin Haematol. 2008;21(1):1-3.
3. Gilliland DG. Targeted therapies in myeloid leukemias. Ann Hematol. 2004;83 (Suppl 1):S75-6.
4. Jordan CT. Searching for leukemia stem cells--not yet the end of the road? Cancer Cell. 2006;10(4):253-4.
5. Jordan CT. The leukemic stem cell. Best Pract Res Clin Haematol. 2007;20(1):13-8.
6. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in selfrenewal capacity. Nat Immunol. 2004; 5(7):738-43.
7. Gilliland DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol. 2002;39(4 Suppl 3):6-11.
8. Wu J, Wong WW, Khosravi F, Minden MD, Penn LZ. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res. 2004;64(18):6461-8.
9. Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood. 2005;106(3):1063-6.
10. Tamburini J, Elie C, Bardet V, Chapuis N, Park S, Broet P, et al. Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. Blood. 2007;110(3):1025-8.
11. dos Santos C, Recher C, Demur C, Payrastre B. [The PI3K/Akt/mTOR pathway: a new therapeutic target in the treatment of acute myeloid leukemia]. Bull Cancer. 2006;93(5):445-7.
12. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Basecke J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008; 22(4):686-707.
13. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007; 1773(8):1263-84.
14. De Toni F, Racaud-Sultan C, Chicanne G, Mas VM, Cariven C, Mesange F, et al. A crosstalk between the Wnt and the adhesiondependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. Oncogene. 2006;25(22):3113-22.
15. Petropoulos K, Arseni N, Schessl C, Stadler CR, Rawat VP, Deshpande AJ, et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Med. 2008;205(3):515-22.
16. Valencia A, Roman-Gomez J, Cervera J, Such E, Barragan E, Bolufer P, et al. Wnt signaling pathway is epigenetically regulated by methylation of Wnt antagonists in acute myeloid leukemia. Leukemia. 2009;23(9): 1658-66.
17. Griessinger E, Imbert V, Lagadec P, Gonthier N, Dubreuil P, Romanelli A, et al. AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells. Leukemia. 2007;21(5):877-85.
18. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001;98(8): 2301-7.
19. Guzman ML, Swiderski CF, Howard DS, Grimes BA, Rossi RM, Szilvassy SJ, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci USA. 2002;99(25):16220-5.
20. Baumgartner B, Weber M, Quirling M, Fischer C, Page S, Adam M, et al. Increased IkappaB kinase activity is associated with activated NF-kappaB in acute myeloid blasts. Leukemia. 2002;16(10):2062-71.
21. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550-62.
22. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27(41):5497-510.
23. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans. 2006;34(Pt 5):647-62.
24. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007; 129(7):1261-74.
25. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 2007;318(5852):977-80.
26. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005; 24(50):7410-25.
27. Scheijen B, Ngo HT, Kang H, Griffin JD. FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oncogene. 2004;23(19):3338-49.
28. Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol. 1999;11(2):219-25.
29. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95(1):29-39.
30. Gao T, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell. 2005; 18(1):13-24.
31. Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP. Identification of a tumour suppressor network opposing nuclear Akt function. Nature. 2006;441(7092):523-7.
32. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005;15(8):702-13.
33. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648-57.
34. Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci. 2006; 31(6):342-8.
35. Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123(4): 569-80.
36. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23(18):3189-99.
37. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166(2):213-23.
38. Kwon J, Stephan S, Mukhopadhyay A, Muders MH, Dutta SK, Lau JS, et al. Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. Cancer Res. 2009;69(4): 1350-7.
39. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-101.
40. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008;416(3): 375-85.
41. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to AktFOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859-71.
42. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006; 22(2):159-68.
43. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137(5):873-86.
44. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475-82.
45. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441(7092):518-22.
46. Myklebust JH, Blomhoff HK, Rusten LS, Stokke T, Smeland EB. Activation of phosphatidylinositol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34(+) hematopoietic progenitor cells. Exp Hematol. 2002;30(9):990-1000.
47. Bouscary D, Pene F, Claessens YE, Muller O, Chretien S, Fontenay-Roupie M, et al. Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood. 2003;101(9):3436-43.
48. Buitenhuis M, Verhagen LP, van Deutekom HW, Castor A, Verploegen S, Koenderman L, et al. Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood. 2008;111(1): 112-21.
49. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, et al. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med. 2008;205(10):2397-408.
50. Gan B, Sahin E, Jiang S, Sanchez-Aguilera A, Scott KL, Chin L, et al. mTORC1- dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci USA. 2008;105(49):19384-9.
51. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325-39.
52. Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003;102(3):972-80.
53. Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 2003;17(5): 995-7.
54. 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-kappaB, Mapkinase and p53 pathways. Leukemia. 2005;19(4):586-94.
55. Gallay N, dos Santos C, Cuzin L, Bousquet M, Simmonet Gouy V, Chaussade C, 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(6):1029-38.
56. Bardet V, Tamburini J, Ifrah N, Dreyfus F, Mayeux P, Bouscary D, et al. Single cell analysis of phosphoinositide 3-kinase/Akt and ERK activation in acute myeloid leukemia by flow cytometry. Haematologica. 2006;91(6):757-64.
57. Recher C, Beyne-Rauzy O, Demur C, Chicanne G, dos Santos C, Mas VM, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005; 105(6):2527-34.
58. Recher C, dos Santos C, Demur C, Payrastre B. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle. 2005;4(11):1540-9.
59. Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood. 2005;106(13):4261-8.
60. Tamburini J, Green AS, Bardet V, Chapuis N, Park S, Willems L, et al. Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia. Blood. 2009;114(8): 1618-27.
61. Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B, et al. A selective inhibitor of the p110delta isoform of PI 3- kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene. 2006;25(50):6648-59.
62. 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(9):1921-30.
63. 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(3):1027-36.
64. Kang S, Denley A, Vanhaesebroeck B, Vogt PK. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci USA. 2006;103(5):1289-94.
65. Kok K, Nock GE, Verrall EA, Mitchell MP, Hommes DW, Peppelenbosch MP, et al. Regulation of p110delta PI 3-kinase gene expression. PLoS One. 2009;4(4):e5145.
66. Bousquet M, Recher C, Queleen C, Demur C, Payrastre B, Brousset P. Assessment of somatic mutations in phosphatidylinositol 3-kinase gene in human lymphoma and acute leukaemia. Br J Haematol. 2005; 131(3):411-3.
67. Cornillet-Lefebvre P, Cuccuini W, Bardet V, Tamburini J, Gillot L, Ifrah N, et al. Constitutive phosphoinositide 3-kinase activation in acute myeloid leukemia is not due to p110delta mutations. Leukemia. 2006;20(2):374-6.
68. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446(7132): 153-8.
69. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448(7152):439-44.
70. Tibes R, Kornblau SM, Qiu Y, Mousses SM, Robbins C, Moses T, et al. PI3K/AKT pathway activation in acute myeloid leukaemias is not associated with AKT1 pleckstrin homology domain mutation. Br J Haematol. 2008;140(3):344-7.
71. Luo JM, Yoshida H, Komura S, Ohishi N, Pan L, Shigeno K, et al. Possible dominantnegative mutation of the SHIP gene in acute myeloid leukemia. Leukemia. 2003;17(1):1-8.
72. Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, 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(3):454-6.
73. Metzner A, Precht C, Fehse B, Fiedler W, Stocking C, Gunther A, et al. Reduced proliferation of CD34(+) cells from patients with acute myeloid leukemia after gene transfer of INPP5D. Gene Ther. 2009; 16(4):570-3.
74. Pedersen M, Ronnstrand L, Sun J. The cKit/D816V mutation eliminates the differences in signal transduction and biological responses between two isoforms of c-Kit. Cell Signal. 2009;21(3):413-8.
75. Sun J, Pedersen M, Ronnstrand L. Gab2 is involved in differential phosphoinositide 3- kinase signaling by two splice forms of cKit. J Biol Chem. 2008;283(41):27444-51.
76. Tazzari PL, Tabellini G, Bortul R, Papa V, Evangelisti C, Grafone T, et al. The insulinlike 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(5):886-96.
77. Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. 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(1):379-82.
78. Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, et al. Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica. 2010;95(3):415-23.
79. List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bellamy W, Powis G. Vascular endothelial growth factor receptor-1 and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid leukemia cells. Exp Hematol. 2004;32(6):526-35.
80. Wakabayashi M, Miwa H, Shikami M, Hiramatsu A, Ikai T, Tajima E, et al. Autocrine pathway of angiopoietins-Tie2 system in AML cells: association with phosphatidyl-inositol 3 kinase. Hematol J. 2004;5(4):353-60.
81. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, 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(9): 1158-65.
82. Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007;109(8):3509-12.
83. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, 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(2):684-94.
84. dos Santos C, Demur C, Bardet V, PradeHoudellier N, Payrastre B, Recher C. A critical role for Lyn in acute myeloid leukemia. Blood. 2008;111(4):2269-79.
85. 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(9):1183-91.
86. Zhong D, Liu X, Khuri FR, Sun SY, Vertino PM, Zhou W. LKB1 is necessary for Aktmediated phosphorylation of proapoptotic proteins. Cancer Res. 2008;68(18):7270-7.
87. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006;125(4):733-47.
88. Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia. 2008;22(9): 1698-706.
89. Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, 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(9):1728-36.
90. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284(12):8023-32.
91. Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood. 2006;108(7):2358-65.
92. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, et al. Essential role for the p110delta phosphoinositide 3- kinase in the allergic response. Nature. 2004;431(7011):1007-11.
93. Okkenhaug K, Ali K, Vanhaesebroeck B. Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K. Trends Immunol. 2007;28(2):80-7.
94. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, et al. Active-site inhibitors of mTOR target rapamycinresistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.
95. Garcia-Martinez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J. 2009;421(1):29-42.
96. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, 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(7):1851-63.
97. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVPBEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68(19):8022-30.
98. Sato S, Fujita N, Tsuruo T. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene. 2002;21(11):1727-38.
99. Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM. Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositidedependent protein kinase-1) inhibition. Biochem J. 2003;375(Pt 2):255-62.
100. Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, 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(6):2517-24.
101. Gills JJ, Dennis PA. The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt. Expert Opin Investig Drugs. 2004; 13(7):787-97.
102. Gills JJ, Castillo SS, Zhang C, Petukhov PA, Memmott RM, Hollingshead M, et al. Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. J Biol Chem. 2007;282(37): 27020-9.
103. Memmott RM, Gills JJ, Hollingshead M, Powers MC, Chen Z, Kemp B, et al. Phosphatidylinositol ether lipid analogues induce AMP-activated protein kinasedependent death in LKB1-mutant non small cell lung cancer cells. Cancer Res. 2008; 68(2):580-8.
104. Papa V, Tazzari PL, Chiarini F, Cappellini A, Ricci F, Billi AM, et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia. 2008; 22(1):147-60.
105. Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, et al. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res. 2008;68(22):9394-403.
106. Bortul R, Tazzari PL, Billi AM, Tabellini G, Mantovani I, Cappellini A, et al. Deguelin, a PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway. Br J Haematol. 2005;129(5):677-86.
107. Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, et al. Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood. 2007;110(6): 1942-9.
108. Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res. 2006;66(7):3737-46.
109. Weisberg E, Banerji L, Wright RD, Barrett R, Ray A, Moreno D, 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(7):3723-34.
110. Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC, et al. Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene. 2005;24(24):3954-63.
111. George P, Bali P, Cohen P, Tao J, Guo F, Sigua C, et al. Cotreatment with 17-allylaminodemethoxygeldanamycin and FLT- 3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res. 2004;64(10):3645-52.
112. George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105(4):1768-76.
113. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627-44.
114. Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood. 2009;114(6):1150-7.
115. Weisberg E, Barrett R, Liu Q, Stone R, Gray N, Griffin JD. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3- positive AML. Drug Resist Updat. 2009; 12(3):81-9.