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Acute Leukemias

PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML

Leukemia volume 22, pages 1698–1706 (2008)Cite this article

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways are frequently activated in acute myelogenous leukemia (AML). mTORC1 inhibition with RAD001 induces PI3K/Akt activation and both pathways are activated independently, providing a rationale for dual inhibition of both pathways. PI-103 is a new potent PI3K/Akt and mTOR inhibitor. In human leukemic cell lines and in primary blast cells from AML patients, PI-103 inhibited constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 was essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibited leukemic proliferation, the clonogenicity of leukemic progenitors and induced mitochondrial apoptosis, especially in the compartment containing leukemic stem cells. In contrast, apoptosis was not induced with RAD001 and IC87114 association, which specifically inhibits mTORC1 and p110δ activity, respectively. PI-103 had additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. Interestingly, PI-103 did not induce apoptosis in normal CD34+ cells and had moderate effects on their clonogenic and proliferative properties. Here, we demonstrate that multitargeted therapy against PI3K/Akt and mTOR with PI-103 may be of therapeutic value in AML.

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Acknowledgements

We thank Dr Cecile Demur and Dr Christian Recher for providing the bladder carcinoma cell line 5637. SP is a recipient of grants from Assistance Publique des Hôpitaux de Paris/La Caisse Nationale d'Assurance Maladie (APHP/CANAM) and Fondation de France. This work was supported by l'Association Laurette Fugain, the Ligue Nationale contre le Cancer (LNCC, laboratoire associé), the Institut National du Cancer (INCA) and NIH R01 AI44009. SP performed research, analyzed the data and wrote the paper; NC, VB JT and LW performed research and analyzed the data; FD, NI and NA analyzed the clinical data; FV performed cytogenetic analysis of AML samples; FD and NI provided AML samples; CL and PM analyzed the data and wrote the paper; DB designed the research, analyzed the data and wrote the paper.

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Authors and Affiliations

  1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France

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

  2. Inserm U567, Paris, France

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

  3. Service de Médecine Interne–UF d'Hématologie, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France

    S Park, J Tamburini, F Dreyfus & D Bouscary

  4. Laboratoire d'Hématologie, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France

    V Bardet & C Lacombe

  5. Centre de Physiopathologie de Toulouse Purpan, INSERM U563, CHU Purpan, Toulouse, France

    N Gallay

  6. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA

    Z A Knight & K M Shokat

  7. Service d'Hématologie, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Paris, France

    N Azar

  8. Laboratoire d'Hématologie, Assistance Publique–Hôpitaux de Paris, Hôpital Hôtel-Dieu, Paris, France

    F Viguié

  9. Service d'hématologie, CHU d'Angers, Angers, France

    N Ifrah

  10. GOELAMS: Groupe Ouest Est d'étude des Leucémies et Autres Maladies du Sang,

    S Park, V Bardet, N Ifrah, F Dreyfus, C Lacombe & D Bouscary

Authors
  1. S Park
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  2. N Chapuis
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Correspondence to D Bouscary.

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Park, S., Chapuis, N., Bardet, V. et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22, 1698–1706 (2008). https://doi.org/10.1038/leu.2008.144

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