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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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NEOPLASIA

Brief Report

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

Jerome Tamburini1,4, Nicolas Chapuis1,3,5, Valérie Bardet1,3,5, Sophie Park1,4, Pierre Sujobert1,4, Lise Willems1,3, Norbert Ifrah6, François Dreyfus1,4, Patrick Mayeux1,3, Catherine Lacombe1,5, and Didier Bouscary1,4

1 Institut Cochin, Département d'Hématologie, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), Paris; 2 Inserm U567, Paris; 3 Université Paris Descartes, Faculté de Médecine René Descartes, Paris; 4 Service de Médecine Interne, UF d'Hématologie, Assistance Publique-Hôpitaux de Paris; Hôpital Cochin, Paris; 5 Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Paris; and 6 Service des Maladies du Sang, Centre Hospitalier Universitaire, Angers, France

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.


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