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