Mammalian target of rapamycin inhibition as therapy for hematologic malignancies.
The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway, which mediates cell survival and proliferation. mTOR regulates essential signal-transduction pathways, is involved in the coupling of growth stimuli with cell cycle progression, and initiates mRNA translation in response to favorable nutrient environments. mTOR is involved in regulating many aspects of cell growth, including membrane traffic, protein degradation, protein kinase C signaling, ribosome biogenesis, and transcription. Because mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein 1, its inhibitors cause G1-phase cell cycle arrest. Inhibitors of mTOR also prevent cyclin dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause G1-phase arrest. It is known that the phosphatase and tensin homologue tumor suppressor gene (PTEN) plays a major role in embryonic development, cell migration, and apoptosis. Malignancies with PTEN mutations, which are associated with constitutive activation of the PI3K/Akt pathway, are relatively resistant to apoptosis and may be particularly sensitive to mTOR inhibitors. Rapamycin analogs with relatively favorable pharmaceutical properties, including CCI-779, RAD001, and AP23573, are under investigation in patients with hematologic malignancies.
Panwalkar
Amit
A
Section of Developmental Therapeutics, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Verstovsek
Srdan
S
Giles
Francis J
FJ
D017209:Apoptosis; D002455:Cell Division; D002470:Cell Survival; D018844:Cyclin-Dependent Kinases / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000494:pharmacology; D011494:Protein Kinases / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000494:pharmacology
D007166:Immunosuppressive Agents; D025521:Tumor Suppressor Proteins; C401859:temsirolimus; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus