Abstract
Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment to regulate multiple cellular processes. Rapamycin and its analogs have not shown significant activity in multiple myeloma (MM), likely because of the lack of inhibition of TORC2. In the present study, we investigated the baseline activity of the PI3K/Akt/mTOR pathway TORC1/2 in MM cell lines with different genetic abnormalities. TORC1/2 knock-down led to significant inhibition of the proliferation of MM cells, even in the presence of BM stromal cells. We also tested INK128, a dual TORC1/2 inhibitor, as a new therapeutic agent against these MM cell lines. We showed that dual TORC1/2 inhibition is much more active than TORC1 inhibition alone (rapamycin), even in the presence of cytokines or stromal cells. In vitro and in vivo studies showed that p-4EBP1 and p-Akt inhibition could be predictive markers of TORC2 inhibition in MM cell lines. Dual TORC1/2 inhibition showed better inhibition of adhesion to BM microenvironmental cells and inhibition of homing in vivo. These studies form the basis for further clinical testing of TORC1/2 inhibitors in MM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects
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Blotting, Western
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, SCID
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Multiple Myeloma / drug therapy
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Multiple Myeloma / metabolism*
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Multiple Myeloma / pathology
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Multiprotein Complexes
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proteins / antagonists & inhibitors
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Proteins / genetics
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Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Rapamycin-Insensitive Companion of mTOR Protein
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Regulatory-Associated Protein of mTOR
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Carrier Proteins
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Multiprotein Complexes
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Phosphoproteins
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Protein Kinase Inhibitors
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Proteins
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RICTOR protein, human
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RPTOR protein, human
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Rapamycin-Insensitive Companion of mTOR Protein
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Regulatory-Associated Protein of mTOR
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus