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Blood, 1 January 2008, Vol. 111, No. 1, pp. 379-382.
Prepublished online as a Blood First Edition Paper on September 18, 2007; DOI 10.1182/blood-2007-03-080796.
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Submitted March 19, 2007
Accepted September 12, 2007
mTORC1 inhibition activates PI3K/Akt by up-regulating IGF-1R signaling in acute myeloid leukemia: rational for therapeutic inhibition of both pathways
Jerome Tamburini, Nicolas Chapuis, Valerie Bardet, Sophie Park, Pierre Sujobert, Lise Willems, Norbert Ifrah, Francois Dreyfus, Patrick Mayeux, Catherine Lacombe, and Didier Bouscary*
Institut Cochin, Departement d'Hematologie, CNRS (UMR8104), Paris, France
INSERM, U567, Paris, France
Faculte de Medecine Rene Descartes, University Paris Descartes, Paris, France
Service de Medecine Interne - UF d'Hematologie, AP-HP, Hopital Cochin, Paris, France
Service des Maladies du Sang, CHU Angers, Angers, France
Service d'Hematologie Biologique, AP-HP, Paris, France
* Corresponding author; email: bouscary{at}cochin.inserm.fr.
The PI3K/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukaemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTORC1-mediated Akt up-regulation was explained by an IGF-1/IGF-1 receptor autocrine loop: a/ blast cells expressed functional IGF-1 receptors, and IGF-1-induced Akt activation was increased by RAD001, b/ a neutralizing anti-IGF-1R alpha-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, c/ autocrine production of IGF-1 was detected in purified blast cells by quantitative RT-PCR 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.
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