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

Leukemia. 2012 Jun;26(6):1195-202. doi: 10.1038/leu.2011.339. Epub 2011 Dec 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / prevention & control*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Morpholines / pharmacology*
  • Multiprotein Complexes
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Survival Rate
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • CRTC2 protein, human
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Morpholines
  • Multiprotein Complexes
  • Phosphoproteins
  • Proteins
  • Transcription Factors
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1