Dual Inhibition of PI3K and mTORC1/2 Signaling by NVP-BEZ235 as a New Therapeutic Strategy for Acute Myeloid Leukemia

被引：134

作者：

Chapuis, Nicolas ^{[2
,3
]}

Tamburini, Jerome ^{[2
,4
]}

Green, Alexa S. ^{[2
]}

Vignon, Christine ^{[5
]}

Bardet, Valerie ^{[2
,3
]}

Neyret, Aymeric ^{[2
]}

Pannetier, Melanie ^{[2
]}

Willems, Lise ^{[2
,4
]}

Park, Sophie ^{[2
,4
]}

Macone, Alexandre ^{[2
]}

Maira, Sauveur-Michel ^{[7
]}

Ifrah, Norbert ^{[8
]}

Dreyfus, Francois ^{[2
,4
]}

Herault, Olivier ^{[6
]}

Lacombe, Catherine ^{[2
,3
]}

Mayeux, Patrick ^{[2
]}

Bouscary, Didier ^{[1
,2
,4
]}

机构：

[1] Univ Paris 05, Inst Cochin, Dept Hematol Immunol, CNRS,UMR8104, F-75014 Paris, France

[2] INSERM, U1016, Paris, France

[3] Hop Cochin, AP HP, Serv Hematol Biol, F-75674 Paris, France

[4] Hop Cochin, AP HP, Serv Med Interne UF Hematol, F-75674 Paris, France

[5] Univ Tours, UPRES EA3855, Tours, France

[6] CHRU Tours, Serv Hematol Biol, Tours, France

[7] Novartis Inst Biomed Res, Basel, Switzerland

[8] CHU Angers, Serv Malad Sang, Angers, France

来源：

CLINICAL CANCER RESEARCH | 2010年 / 16卷 / 22期

关键词：

PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; MAMMALIAN TARGET; TRANSLATION INITIATION; ANTILEUKEMIC ACTIVITY; RAPAMYCIN INHIBITOR; CELL-PROLIFERATION; P110-DELTA ISOFORM; BINDING PARTNER; PROTEIN-KINASE; COMPLEX;

D O I：

10.1158/1078-0432.CCR-10-1102

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The growth and survival of acute myeloid leukemia (AML) cells are enhanced by the deregulation of signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR). Major efforts have thus been made to develop molecules targeting these activated pathways. The mTOR serine/threonine kinase belongs to two separate complexes: mTORC1 and mTORC2. The mTORC1 pathway is rapamycin sensitive and controls protein translation through the phosphorylation of 4E-BP1 in most models. In AML, however, the translation process is deregulated and rapamycin resistant. Furthermore, the activity of PI3K/Akt and mTOR is closely related, as mTORC2 activates the oncogenic kinase Akt. We therefore tested, in this study, the antileukemic activity of the dual PI3K/mTOR ATP-competitive inhibitor NVP-BEZ235 compound (Novartis). Experimental Design: The activity of NVP-BEZ235 was tested in primary AML samples (n = 21) and human leukemic cell lines. The different signaling pathways were analyzed by Western blotting. The cap-dependent mRNA translation was studied by 7-methyl-GTP pull-down experiments, polysomal analysis, and [H-3] leucine incorporation assays. The antileukemic activity of NVP-BEZ235 was tested by analyzing its effects on leukemic progenitor clonogenicity, blast cell proliferation, and survival. Results: The NVP-BEZ235 compound was found to inhibit PI3K and mTORC1 signaling and also mTORC2 activity. Furthermore, NVP-BEZ235 fully inhibits the rapamycin-resistant phosphorylation of 4E-BP1, resulting in a marked inhibition of protein translation in AML cells. Hence, NVP-BEZ235 reduces the proliferation rate and induces an important apoptotic response in AML cells without affecting normal CD34(+) survival. Conclusions: Our results clearly show the antileukemic efficiency of the NVP-BEZ235 compound, which therefore represents a promising option for future AML therapies. Clin Cancer Res; 16(22); 5424-35. (C) 2010 AACR.

引用

页码：5424 / 5435

页数：12

共 50 条

[41] mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action [J].

Soliman, Ghada A. ;

Acosta-Jaquez, Hugo A. ;

Dunlop, Elaine A. ;

Ekim, Bilgen ;

Maj, Nicole E. ;

Tee, Andrew R. ;

Fingar, Diane C. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (11) :7866-7879

[42] Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia [J].

Sujobert, P ;

Bardet, V ;

Cornillet-Lefebvre, P ;

Hayflick, JS ;

Prie, N ;

Verdier, F ;

Vanhaesebroeck, B ;

Muller, O ;

Pesce, F ;

Ifrah, N ;

Hunault-Berger, M ;

Berthou, C ;

Villemagne, B ;

Jourdan, E ;

Audhuy, B ;

Solary, E ;

Witz, B ;

Harousseau, JL ;

Himberlin, C ;

Lamy, T ;

Lioure, B ;

Cahn, JY ;

Dreyfus, F ;

Mayeux, P ;

Lacombe, C ;

Bouscary, D .

BLOOD, 2005, 106 (03) :1063-1066

[43] 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 [J].

Tamburini, Jerome ;

Chapuis, Nicolas ;

Bardet, Valrie ;

Park, Sophie ;

Sujobert, Pierre ;

Willems, Lise ;

Ifrah, Norbert ;

Dreyfus, Francois ;

Mayeux, Patrick ;

Lacombe, Catherine ;

Bouscary, Didier .

BLOOD, 2008, 111 (01) :379-382

[44] Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients [J].

Tamburini, Jerome ;

Elie, Caroline ;

Bardet, Valerie ;

Chapuis, Nicolas ;

Park, Sophie ;

Broet, Philippe ;

Cornillet-Lefebvre, Pascale ;

Lioure, Bruno ;

Ugo, Valerie ;

Blanchet, Odile ;

Ifrah, Norbert ;

Witz, Francis ;

Dreyfus, Francois ;

Mayeux, Patrick ;

Lacombe, Catherine ;

Bouscary, Didier .

BLOOD, 2007, 110 (03) :1025-1028

[45] Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia [J].

Tamburini, Jerome ;

Green, Alexa S. ;

Bardet, Valerie ;

Chapuis, Nicolas ;

Park, Sophie ;

Willems, Lise ;

Uzunov, Madalina ;

Ifrah, Norbert ;

Dreyfus, Francois ;

Lacombe, Catherine ;

Mayeux, Patrick ;

Bouscary, Didier .

BLOOD, 2009, 114 (08) :1618-1627

[46] An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1 [J].

Thoreen, Carson C. ;

Kang, Seong A. ;

Chang, Jae Won ;

Liu, Qingsong ;

Zhang, Jianming ;

Gao, Yi ;

Reichling, Laurie J. ;

Sim, Taebo ;

Sabatini, David M. ;

Gray, Nathanael S. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (12) :8023-8032

[47] Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4E phosphorylation [J].

Wang, Xuerong ;

Yue, Ping ;

Chan, Chi-Bun ;

Ye, Keqiang ;

Ueda, Takeshi ;

Watanabe-Fukunaga, Rie ;

Fukunaga, Rikiro ;

Fu, Haian ;

Khuri, Fadlo R. ;

Sun, Shi-Yong .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (21) :7405-7413

[48] Survival of acute myeloid leukemia cells requires PI3 kinase activation [J].

Xu, Q ;

Simpson, SE ;

Scialla, TJ ;

Bagg, A ;

Carroll, M .

BLOOD, 2003, 102 (03) :972-980

[49] Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin [J].

Yu, Ker ;

Toral-Barza, Lourdes ;

Shi, Celine ;

Zhang, Wei-Guo ;

Lucas, Judy ;

Shor, Boris ;

Kim, Jamie ;

Verheijen, Jeroen ;

Curran, Kevin ;

Malwitz, David J. ;

Cole, Derek C. ;

Ellingboe, John ;

Ayral-Kaloustian, Semiramis ;

Mansour, Tarek S. ;

Gibbons, James J. ;

Abraham, Robert T. ;

Nowak, Pawel ;

Zask, Arie .

CANCER RESEARCH, 2009, 69 (15) :6232-6240

[50] Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML [J].

Zeng, Zhihong ;

Sarbassov, Dos D. ;

Samudio, Ismael J. ;

Yee, Karen W. L. ;

Munsell, Mark F. ;

Jackson, C. Ellen ;

Giles, Francis J. ;

Sabatini, David M. ;

Andreeff, Michael ;

Konopleva, Marina .

BLOOD, 2007, 109 (08) :3509-3512

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