Cellular and molecular effects of the mTOR inhibitor everolimus.
mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.
Hepatology, Department of Clinical Research, University of Berne, Switzerland University Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland.
Uttara
U
Saran
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Michelangelo
M
Foti
Hepatology, Department of Clinical Research, University of Berne, Switzerland University Clinic of Visceral Surgery and Medicine, Inselspital, Berne, Switzerland jf.dufour@insel.ch.
Jean-François
JF
Dufour
D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D000068338:Everolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
4E-BP1; Cancer; Drug Mechanisms of Action; Epigenetics; S6K1; Signalling; everolimus; mTOR; mTORC1; rapamycin