The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia

被引：135

作者：

Willems, L. ^{[1
,2
,3
]}

Chapuis, N. ^{[1
,2
,4
]}

Puissant, A. ^{[5
]}

Maciel, T. T. ^{[6
]}

Green, A. S. ^{[1
,2
,7
]}

Jacque, N. ^{[1
,2
]}

Vignon, C. ^{[8
]}

Park, S. ^{[1
,2
,3
]}

Guichard, S. ^{[10
]}

Herault, O. ^{[8
]}

Fricot, A. ^{[6
]}

Hermine, O. ^{[9
]}

Moura, I. C. ^{[6
]}

Auberger, P. ^{[5
]}

Ifrah, N. ^{[11
,12
]}

Dreyfus, F. ^{[1
,2
,3
,12
]}

Bonnet, D. ^{[13
]}

Lacombe, C. ^{[1
,2
,4
]}

Mayeux, P. ^{[1
,2
]}

Bouscary, D. ^{[1
,2
,3
,12
]}

Tamburini, J. ^{[1
,2
,3
]}

机构：

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

[2] INSERM, U1016, Paris, France

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

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

[5] Ctr Hosp Univ Nice, Lab Hematol Clin & Transplantat, INSERM895, Team Cell Death Differentiat & Canc 2, Nice, France

[6] INSERM, Fac Med Xavier Bichat, U699, Paris, France

[7] Hop Charles Nicolle, Serv Hematol Biol, Rouen, France

[8] Univ Tours, UPRES, EA3855, CHRU Tours,Serv Hematol Biol, Tours, France

[9] Hop Necker Enfants Malad, AP HP, Serv Hematol, Paris, France

[10] AstraZeneca Canc & Infect Res Area, Alderley Pk, England

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

[12] CHU Bretonneau, GOELAMS, F-37044 Tours, France

[13] Canc Res UK, Hematopoiet Stem Cell Lab, London, England

来源：

LEUKEMIA | 2012年 / 26卷 / 06期

关键词：

mTOR; AML; AZD8055; protein translation; autophagy; apoptosis; MAMMALIAN TARGET; KINASE INHIBITOR; CELL-DEATH; PROTEIN-SYNTHESIS; RAPAMYCIN; PHOSPHORYLATION; ACTIVATION; AUTOPHAGY; TRANSLATION; EXPRESSION;

D O I：

10.1038/leu.2011.339

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.

引用

页码：1195 / 1202

页数：8