Submitted June 22, 2006
Accepted November 29, 2006
Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML
Zhihong Zeng, Dos D Sarbassov, Ismael J Samudio, Karen WL Yee, Mark F Munsell, C Ellen Jackson, Francis J Giles, David M Sabatini, Michael Andreeff, and Marina Konopleva*
Section of Molecular Hematology and Therapy, Dept of Stem Cell Transplantation & Cellular Therapy University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Biology, Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, United States
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Biochemistry, The Broad Institute, Cambridge, MA, United States
* Corresponding author; email: mkonople{at}mdanderson.org.
The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin-insensitive, and was recently shown to regulate the pro-survival 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 AML cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation and glut-1 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 hematological malignancies who received RDs in clinical studies. Our study provides first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and support the therapeutic potential of mTOR inhibition strategies in leukemias.
