Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML

Zhihong Zeng, Dos D. Sarbassov, Ismael J. Samudio, Karen W L Yee, Mark F. Munsell, C. Ellen Jackson, Francis J. Giles, David M. Sabatini, Michael Andreeff, Marina Konopleva*

*Corresponding author for this work

Research output: Contribution to journalArticle

280 Scopus citations

Abstract

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.

Original languageEnglish (US)
Pages (from-to)3509-3512
Number of pages4
JournalBlood
Volume109
Issue number8
DOIs
StatePublished - Apr 15 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Zeng, Z., Sarbassov, D. D., Samudio, I. J., Yee, K. W. L., Munsell, M. F., Jackson, C. E., Giles, F. J., Sabatini, D. M., Andreeff, M., & Konopleva, M. (2007). Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood, 109(8), 3509-3512. https://doi.org/10.1182/blood-2006-06-030833