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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

Tamburini, Jerome, Chapuis, Nicolas, Bardet, Valérie, Park, Sophie, Sujobert, Pierre, Willems, Lise, Ifrah, Norbert, Dreyfus, François, Mayeux, Patrick, Lacombe, Catherine, Bouscary, Didier·2008·Blood
DOI 10.1182/blood-2007-03-080796
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Abstract

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 α-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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Research works printed but not linked: 18

  1. Min, 2003, Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable., Leukemia, 17, 995, 10.1038/sj.leu.2402874 · DOI · Paper page
  2. Xu, 2003, Survival of acute myeloid leukemia cells requires PI3 kinase activation., Blood, 102, 972, 10.1182/blood-2002-11-3429 · DOI · Paper page
  3. Zhao, 2004, Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias., Leukemia, 18, 267, 10.1038/sj.leu.2403220 · DOI
  4. Bardet, 2006, Single cell analysis of phosphoinositide 3-kinase/Akt and ERK activation in acute myeloid leukemia by flow cytometry., Haematologica, 91, 757
  5. Tamburini, 2007, Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients., Blood, 110, 1025, 10.1182/blood-2006-12-061283 · DOI · Paper page
  6. Billottet, 2006, A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16., Oncogene, 25, 6648, 10.1038/sj.onc.1209670 · DOI
  7. Sujobert, 2005, Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia., Blood, 106, 1063, 10.1182/blood-2004-08-3225 · DOI
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Metadata

Authors
Tamburini, J., Chapuis, N., Bardet, V., Park, S., Sujobert, P., Willems, L., Ifrah, N., Dreyfus, F., Mayeux, P., Lacombe, C., & Bouscary, D.
Venue
Blood
Publisher
American Society of Hematology
Published
2008-01-01
Volume
111
Issue
1
Pages
379-382
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2007-03-080796
Cited by
221
References
0
Language
en

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CoChat. (2026). Citation check: 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. https://app.cochat.ai/papers/10.1182/blood-2007-03-080796
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Tamburini, J., Chapuis, N., Bardet, V., Park, S., Sujobert, P., Willems, L., Ifrah, N., Dreyfus, F., Mayeux, P., Lacombe, C., & Bouscary, D. (2008). 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. Blood. https://doi.org/10.1182/blood-2007-03-080796