Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy.
The mTORC1 signaling pathway is a critical regulator of cell growth and is hyper activated in many different cancers. Rapamycin, an allosteric inhibitor of mTORC1, has been approved for treatment against renal cell carcinomas and is being evaluated for other cancers. Mechanistically, mTORC1 controls cell growth in part through its two well-characterized substrates S6K1 and 4E-BP1. In this review, we discuss the implications of a recent finding that showed differential inhibition of S6K1 and 4E-BP1 by rapamycin, leading to cell-type-specific repression of cap-dependent translation. We discuss potential mechanisms for this effect, and propose that mTOR-specific kinase inhibitors, instead of rapamycin, should be considered for mTOR-targeted cancer therapy.
Choo
Andrew Y
AY
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Blenis
John
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000378:metabolism*; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus