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.

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. Research Abstract Details 

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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. Abstract Text:

Jerome Tamburini,Nicolas Chapuis, Bardet,Sophie Park,Pierre Sujobert,Lise Willems,Norbert Ifrah, Dreyfus,Patrick Mayeux,Catherine Lacombe,Didier Bouscary,Jerome Tamburini,Nicolas Chapuis, Bardet,Sophie Park,Pierre Sujobert,Lise Willems,Norbert Ifrah, Dreyfus,Patrick Mayeux,Catherine Lacombe,Didier Bouscary,Jerome Tamburini,Nicolas Chapuis,Valérie Bardet,Sophie Park,Pierre Sujobert,Lise Willems,Norbert Ifrah,François Dreyfus,Patrick Mayeux,Catherine Lacombe,Didier Bouscary,

The phosphatidylinositol 3-kinase (PI3K)/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid 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 up-regulation 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 antiproliferative 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.

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. Publishing Authors By Initials

J Tamburini,N Chapuis,V Bardet,S Park,P Sujobert,L Willems,N Ifrah,F Dreyfus,P Mayeux,C Lacombe,D Bouscary,J Tamburini,N Chapuis,V Bardet,S Park,P Sujobert,L Willems,N Ifrah,F Dreyfus,P Mayeux,C Lacombe,D Bouscary,J Tamburini,N Chapuis,V Bardet,S Park,P Sujobert,L Willems,N Ifrah,F Dreyfus,P Mayeux,C Lacombe,D Bouscary,

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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. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Blood

VOLUME: 111

Page Numbers: 379-82

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 18

MONTH: 09

YEAR: 2007

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. Information

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LANGUAGE: eng

NlmUniqueID: 7603509

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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 Related Publications

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