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

被引：213

作者：

Tamburini, Jerome ^{[1
,3
]}

Chapuis, Nicolas ^{[1
,2
,4
]}

Bardet, Valrie ^{[1
,2
,4
]}

Park, Sophie ^{[1
,3
]}

Sujobert, Pierre ^{[1
,3
]}

Willems, Lise ^{[1
,2
]}

Ifrah, Norbert ^{[5
]}

Dreyfus, Francois ^{[1
,3
]}

Mayeux, Patrick ^{[1
,2
]}

Lacombe, Catherine ^{[1
,4
]}

Bouscary, Didier ^{[1
,3
]}

机构：

[1] Ctr Natl Recherche Sci, Inst Cochin, Dept Hematol, Unit Mixt Recherche 8104, Paris, France

[2] Univ Paris 05, Fac Med Rene Descartes, Paris, France

[3] Hop Cochin, Assist Publ Hop Paris, Serv Med Interne UF Hematol, Paris, France

[4] Assist Publ Hop, Serv Hematol Biol, Paris, France

[5] Ctr Hosp Univ, Serv Malad Sang, Angers, France

来源：

BLOOD | 2008年 / 111卷 / 01期

关键词：

D O I：

10.1182/blood-2007-03-080796

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myelold leukemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTOR C1-mediated Akt up-regulation was explained by an insulin-like growth factor-1 (IGF-1)/IGF-1 receptor autocrine loop: (1) blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, (2) a neutralizing anti-IGF-1R alpha-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, and (3) autocrine production of IGF-1 was detected in purified blast cells by quantitative reverse transcription-polymerase chain reaction and immunofluorescence. This RAD001-induced PI3K/Akt upregulation was due to an up-regulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive anti proliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF-1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease.

引用

页码：379 / 382

页数：4

共 18 条

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