Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-07, Vol.107 (28), p.12469-12474
• Main Authors: Carayol, Nathalie, Vakana, Eliza, Sassano, Antonella, Kaur, Surinder, Goussetis, Dennis J., Glaser, Heather, Druker, Brian J., Donato, Nicholas J., Altman, Jessica K., Barr, Sharon, Platanias, Leonidas C., Stark, George R.
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biological Sciences; Cell growth; Cells; Cellular Structures - metabolism; Chronic myeloid leukemia; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene expression; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - pharmacology; Intracellular Signaling Peptides and Proteins - therapeutic use; K562 cells; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Medical treatment; Messenger RNA; Mesylates; Mutation; Mutation - drug effects; Phosphorylation; Phosphorylation - drug effects; Progenitor cells; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - pharmacology; Protein-Serine-Threonine Kinases - therapeutic use; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR Serine-Threonine Kinases
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005114107

mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37/46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2/mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Ph+ ALL.