An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1.
The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1.
Thoreen
Carson C
CC
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Kang
Seong A
SA
Chang
Jae Won
JW
Liu
Qingsong
Q
Zhang
Jianming
J
Gao
Yi
Y
Reichling
Laurie J
LJ
Sim
Taebo
T
Sabatini
David M
DM
Gray
Nathanael S
NS
D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D039642:Eukaryotic Initiation Factors; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins; D012315:RNA Caps / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D007166:Immunosuppressive Agents; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D012315:RNA Caps; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus