Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor.
Although preclinical work with rapalogs suggests potential in treatment of multiple myeloma (MM), they have been less successful clinically. These drugs allostearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin complex (TORC)1. To assess if the mammalian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamycin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex protein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary specimens by immunostaining for AKT phosphorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM effects. These results support TORC2 as a therapeutic target in MM.
Hoang
Bao
B
Division of Hematology Oncology, University of California Los Angeles Greater Los Angeles Veterans Administration (VA) Healthcare Center and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Frost
Patrick
P
Shi
Yijiang
Y
Belanger
Eileen
E
Benavides
Angelica
A
Pezeshkpour
Gholam
G
Cappia
Susanna
S
Guglielmelli
Tommasina
T
Gera
Joseph
J
Lichtenstein
Alan
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology*; D046912:Multiprotein Complexes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000069286:Bortezomib; D058570:TOR Serine-Threonine Kinases