title: 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.affiliation: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Jesse Brown VA Medical Center, Chicago, IL 60611, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Carayol
authors.forename: Eliza
authors.initials: E
authors.lastname: Vakana
authors.forename: Antonella
authors.initials: A
authors.lastname: Sassano
authors.forename: Surinder
authors.initials: S
authors.lastname: Kaur
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Goussetis
authors.forename: Heather
authors.initials: H
authors.lastname: Glaser
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Donato
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.forename: Sharon
authors.initials: S
authors.lastname: Barr
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D022082:Cellular Structures / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus