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Acute Leukemias

The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia

Leukemia volume 26, pages 1195–1202 (2012)Cite this article

Abstract

The serine/threonine kinase mammalian target of rapamycin (mTOR) is crucial for cell growth and proliferation, and is constitutively activated in primary acute myeloid leukemia (AML) cells, therefore representing a major target for drug development in this disease. We show here that the specific mTOR kinase inhibitor AZD8055 blocked mTORC1 and mTORC2 signaling in AML. Particularly, AZD8055 fully inhibited multisite eIF4E-binding protein 1 phosphorylation, subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells. Interestingly, AZD8055 strongly induced autophagy, which may be either protective or cell death inducing, depending on concentration. Finally, AZD8055 markedly increased the survival of AML transplanted mice through a significant reduction of tumor growth, without apparent toxicity. Our current results strongly suggest that AZD8055 should be tested in AML patients in clinical trials.

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Acknowledgements

We thank all participating investigators from the GOELAMS. This work was supported by grants from the Ligue Nationale Contre le Cancer (LNCC, laboratoire associé), the Fondation de France (comité leucémies), the Institut National du Cancer (INCa) and the Association Laurette Fugain. We thank Olivier Thibaudeau (Institut Claude Bernard, Faculté de Médecine Paris Diderot, France) for his assistance on histological sample processing. We thank Dr Nabih Azar, Hôpital de la Pitié-Salpétrière, Paris, France, for his contribution to normal hematopoietic cells collection. INSERM U895 / Team 2 is an Equipe Labellisée par la LNCC (2011-2013).

Author contributions

LW and NC performed the research, analyzed the data and wrote the manuscript; AP performed autophagy experiments; TTM and AF performed mice experiments; ASG performed experiments and analyzed the data; CV performed cell cycle analysis; NJ, SP, SG, OH, OH, ICM and PA analyzed clinical and biological data; NI and FD contributed AML patient samples and analyzed clinical data; CL and PM analyzed the data; DB and JT designed the research, analyzed the data and wrote the manuscript.

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Author notes

  1. L Willems and N Chapuis: These authors contributed equally to this work.

  2. D Bouscary and J Tamburini: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France

    L Willems, N Chapuis, A S Green, N Jacque, S Park, F Dreyfus, C Lacombe, P Mayeux, D Bouscary & J Tamburini

  2. Inserm, U1016, Paris, France

    L Willems, N Chapuis, A S Green, N Jacque, S Park, F Dreyfus, C Lacombe, P Mayeux, D Bouscary & J Tamburini

  3. Service de Médecine Interne-UF d'Hématologie, Hôpital Cochin, AP-HP, Paris, France

    L Willems, S Park, F Dreyfus, D Bouscary & J Tamburini

  4. Service d'Hématologie Biologique, Hôpital Cochin, AP-HP, Paris, France

    N Chapuis & C Lacombe

  5. INSERM895, Team 2: Cell Death Differentiation and Cancer, Laboratoire d'Hématologie Clinique et de Transplantation, Centre Hospitalier Universitaire de Nice, Nice, France

    A Puissant & P Auberger

  6. Inserm U699, Faculté de Médecine Xavier Bichat, Paris, France

    T T Maciel, A Fricot & I C Moura

  7. Service d'Hématologie Biologique, Hôpital Charles Nicolle, Rouen, France

    A S Green

  8. Université François Rabelais, UPRES EA3855, CHRU de Tours, Service d'Hématologie Biologique, Tours, France

    C Vignon & O Herault

  9. AstraZeneca Cancer & Infection Research Area, Alderley Park, UK

    S Guichard

  10. Service d'Hématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France

    O Hermine

  11. Service des Maladies du Sang, CHU Angers, Angers, France

    N Ifrah

  12. Groupe Ouest Est des Leucémies et Autres Maladies du Sang (GOELAMS), CHU Bretonneau, Tours, France

    N Ifrah, F Dreyfus & D Bouscary

  13. Hematopoietic Stem Cell Laboratory, Cancer Research UK, London, UK

    D Bonnet

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  1. L Willems
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  2. N Chapuis
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Corresponding authors

Correspondence to D Bouscary or J Tamburini.

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Competing interests

Sylvie Guichard is an employee of AstraZeneca Cancer & Infection Research Area, Alderley Park, United Kingdom.

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Supplementary Information accompanies the paper on the Leukemia website

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Willems, L., Chapuis, N., Puissant, A. et al. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia 26, 1195–1202 (2012). https://doi.org/10.1038/leu.2011.339

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