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Dual mTORC2/mTORC1 targeting results in potent suppressive effects on Acute Myeloid Leukemia (AML) progenitors
Jessica K. Altman; Antonella Sassano; Surinder Kaur; Heather Glaser; Barbara Kroczynska; Amanda J. Redig; Suzanne Russo; Sharon Barr; Leonidas C. Platanias (Profiled Authors: Jessica K Altman; Surinder Kaur; Barbara Kroczynska; Leonidas C Platanias; Antonella Sassano)
Clinical Cancer Research. 2011;17(13):4378-4388.Abstract
Purpose: To determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. Experimental Design: Combinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation. Results: mTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RImTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro. Conclusions: Dual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selectivemTORC1 targeting with rapamycin. ©2011 AACR.
PMID: 21415215 PMCID: PMC3131493
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