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 Phþ ALL.mRNA translation | cell proliferation | cellular signaling | kinase | OSI-027

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…9 Accordingly, in our current study we tested the anti-leukemic activity of three compounds that directly target the mTOR catalytic domain. Two of these compounds (PP-242 and OSI-027) have already been tested in other hematological cancers, including Philadelphia þ acute leukemias 39,40 and multiple myeloma, 41 and promising preclinical data were reported.…”

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

“…mTORC1 has been shown to control autophagy by direct and indirect mechanisms (32,33). Recently, OSI-027, but not rapamycin, has been shown to profoundly stimulate autophagy in K562 leukemic cells and RCC cell lines (34,35). Alternatively, we have measured caspase-3/7 activation upon OSI-027 or rapamycin treatment to determine whether cell death is mediated by apoptosis.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Also presented in this figure are the sites of action of mTOR inhibitors, some of which have been evaluated in leukemia. 70,71 Akt inhibits tuberous sclerosis 2 (TSC2 or hamartin) function through direct phosphorylation. 72 TSC2 is a GTPase-activating protein that functions in association with the putative TSC1 (or tuberin) to inactivate the small G-protein Rheb.…”