Genetic dissection shows the 4E-BP1-eIF4E axis mediates oncogenic mTOR signalling and is druggable.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Cancer cells; mouse |
| Journal | Cancer cell |
| Year | 2010 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.ccr.2010.01.021 · PMID 20227039 · Free full text (PMC2901095) |
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.
| Intervention | Genetic dissection (4EBP-eIF4E, rpS6) |
| Target | mTOR / 4EBP-eIF4E |
| Model | Cancer cells; mouse |
| Effect | 4EBP-eIF4E (not rpS6) controls cap-dependent translation driving Akt lymphomagenesis – a druggable addiction |