PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.
|Number of pages||13|
|State||Published - Jul 2010|
Bibliographical noteFunding Information:
We thank N. Sonenberg for providing 4E-BP1 constructs, H.G. Wendel for the eIF4E construct, B. Vogelstein and V.E. Velculescu for providing the HCT116 and DLD-1 isogenic cell lines, and E. DeStanchina, H. Zhao, and D. Domingo for technical assistance. This work was supported by NIH Grants P01-CA094060 and P01-CA129243, the Breast Cancer Research Foundation, the Taub Foundation, and the William H. and Alice Goodwin Foundation.
ASJC Scopus subject areas
- Cell Biology
- Cancer Research