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

Abstract

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.

• Authors: Nathalie Carayol, Eliza Vakana, Antonella Sassano, Surinder Kaur, Dennis J Goussetis, Heather Glaser, Brian J Druker, Nicholas J Donato, Jessica K Altman, Sharon Barr, Leonidas C Platanias
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 28 Pg. 12469-74 (Jul 13 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20616057 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• MTOR protein, human
• Fusion Proteins, bcr-abl
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Apoptosis (drug effects, genetics)
• Cellular Structures (metabolism)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, pharmacology, therapeutic use)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics)
• Mutation (drug effects)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (genetics, pharmacology, therapeutic use)
• Signal Transduction (drug effects, genetics)
• Sirolimus (pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases