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Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia

Oncogene volume 32, pages 4331–4342 (2013)Cite this article

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Abstract

The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro-apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects.

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Acknowledgements

GK is supported by the Ligue Nationale contre le Cancer (Equipe labellisée), Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), European Commission (ChemoRes, ArtForce), Fondation de France, Institut National du Cancer (INCa), Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller and the LabEx Immuno-Oncology. EL receives a PhD fellowship from Institut National de la Santé et de la recherche Médicale, AW is supported by a fellowship from Association de recherche sur le cancer (ARC) and MS by Fondation de la Recherche Médicale (FRM).

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Authors and Affiliations

  1. INSERM, U848, Villejuif, France

    E Lainey, A Wolfromm, D Enot, M Scoazec, C Bouteloup, C Leroy, P Fenaux & G Kroemer

  2. Institut Gustave Roussy, Villejuif, France

    E Lainey, A Wolfromm, D Enot, C Bouteloup, C Leroy & L Galluzzi

  3. Hôpital Robert Debré, AP-HP, Paris, France

    E Lainey

  4. Université Paris Diderot/Paris 7, Paris, France

    A Wolfromm

  5. CNRS, UMR8206, Paris, France

    N Marie

  6. INSERM, U705, Paris, France

    N Marie

  7. Laboratoire de Neuropsychopharmacologie des Addictions, Institut Médicament-Toxicologie-Chimie Environnement, Paris, France

    N Marie

  8. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France

    M Scoazec & G Kroemer

  9. Service d’hématologie clinique, Institut Gustave Roussy, Villejuif, France

    J-B Micol & S De Botton

  10. Université Paris Descartes/Paris 5, Sorbonne Paris Cité, Paris, France

    L Galluzzi & G Kroemer

  11. Service d’hématologie clinique, Hôpital Avicenne, AP-HP, Bobigny, France

    P Fenaux

  12. Centre de Recherche des Cordeliers, Paris, France

    G Kroemer

  13. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

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  1. E Lainey
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Correspondence to G Kroemer.

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Lainey, E., Wolfromm, A., Marie, N. et al. Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia. Oncogene 32, 4331–4342 (2013). https://doi.org/10.1038/onc.2012.469

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