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Hsieh AC , Costa M , Zollo O , Davis C , Feldman ME , Testa JR , Meyuhas O , Shokat KM , Ruggero D
Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E
Cancer Cell. 2010 Mar;17(3) :249-261
AbstractWe genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.
NotesHsieh, Andrew C. Costa, Maria Zollo, Ornella Davis, Cole Feldman, Morris E. Testa, Joseph R. Meyuhas, Oded Shokat, Kevan M. Ruggero, Davide Cell press Cambridge 572ck