Mechanisms of resistance to rapamycins.
Rapamycins represent a novel family of anticancer agents, currently including rapamycin and its derivatives, CCI-779 and RAD001. Rapamycins inhibit the function of the mammalian target of rapamycin (mTOR), and potently suppress tumor cell growth by arresting cells in G1 phase or potentially inducing apoptosis of cells, in culture or in xenograft tumor models. However, recent data indicate that genetic mutations or compensatory changes in tumor cells influence the sensitivity of rapamycins. First, mutations of mTOR or FKBP12 prevent rapamycin from binding to mTOR, conferring rapamycin resistance. Second, mutations or defects of mTOR-regulated proteins, including S6K1, 4E-BP1, PP2A-related phosphatases, and p27(Kip1) also render rapamycin insensitivity. In addition, the status of ATM, p53, PTEN/Akt and 14-3-3 are also associated with rapamycin sensitivity. To better explore the role of rapamycins against tumors, this review will summarize the current knowledge of the mechanism of action of rapamycins, and progress in understanding mechanisms of acquired or intrinsic resistance.
Huang
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Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Houghton
P J
PJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005656:Fungal Proteins / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D018809:Proliferating Cell Nuclear Antigen; D029701:Saccharomyces cerevisiae Proteins; C100984:TAP42 protein, S cerevisiae; D025521:Tumor Suppressor Proteins; C413374:p27 antigen; D011494:Protein Kinases; C546842:MTOR protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus