TY - JOUR
T1 - Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E
AU - Hsieh, Andrew C.
AU - Costa, Maria
AU - Zollo, Ornella
AU - Davis, Cole
AU - Feldman, Morris E.
AU - Testa, Joseph R.
AU - Meyuhas, Oded
AU - Shokat, Kevan M.
AU - Ruggero, Davide
PY - 2010/3/16
Y1 - 2010/3/16
N2 - We 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.
AB - We 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=77649286736&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2010.01.021
DO - 10.1016/j.ccr.2010.01.021
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C2 - 20227039
AN - SCOPUS:77649286736
SN - 1535-6108
VL - 17
SP - 249
EP - 261
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -