The molecular target of rapamycin (mTOR) as a therapeutic target against cancer.
The molecular target of rapamycin (mTOR), which is a member of the phosphoinositide 3-kinase related kinase (PIKK) family and a central modulator of cell growth, is a prime strategic target for anti-cancer therapeutic development. mTOR plays a critical role in transducing proliferative signals mediated through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, principally by activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of key mRNAs of proteins required for G(1) to S phase traverse. By targeting mTOR, the immunsuppressant and antiproliferative agent rapamycin (RAP) inhibits signals required for cell cycle progression, cell growth, and proliferation. RAP, a complex macrolide and highly potent fungicide, immunosuppressant, and anti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP gains function by binding to the immunophilin FK506 binding protein 12 (FKBP12) and the resultant complex inhibits the activity of mTOR. Since mTOR activates both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest. RAP also prevents cyclin-dependent kinase (cdk) activation, inhibits retinoblastoma protein ((p)Rb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficienciy of active cdk4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of RAP at the G(1)/S phase transition. Both RAP and several RAP analogs with more favorable pharmaceutical properties have demonstrated prominent growth inhibitory effects against a broad range of human cancers in both preclinical and early clinical evaluations. This review will summarize the principal mechanisms of action of RAP and RAP derivatives and their potential utility of these agents as anti-cancer therapeutics. The preliminary results of early clinical evaluations with RAP analogs and the unique developmental challenges that lie ahead will also be discussed.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D016193:G1 Phase; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A; C087000:EIF4EBP1 protein, human; C546842:MTOR protein, human