4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

Abstract

SUMMARY 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 co-mutation 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.

149 Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS-mutant Cancer Models

“…Consistent with prior results, MEK inhibition alone slowed tumor growth relative to vehicletreated control, but failed to induce tumor regressions ( Figure 4A; She et al, 2010). Although ABT-263 alone had minimal effect on tumor growth, ABT-263/selumetinib led to marked tumor regressions in all 3 KRAS mutant xenografts ( Figures 4A and 4B).…”

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

“…However, the induction of BIM proteins by MEK/ERK inhibition (15,16) can result in BIM being bound and inhibited by anti-apoptotic BCL-2 and/or BCL-XL, which are frequently overexpressed in solid tumors (17). This antagonism may explain the modest apoptotic and largely cytostatic effect of MEK/ERK inhibitors in KRAS mutant tumor xenografts (18) as well as predominantly stable disease in patient studies (6,7). Of note, STAT3 can regulate the transcription of oncogenic and inflammatory genes, including BCL-XL, Myc, cyclin D1, COX-2, and IL-1␤ (19).…”

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

“…Considering all this evidence, we concluded that APP regulates the phosphorylation status of 4E‐BP1 T37/46 through Styx (which is a poorly investigated protein) rather than primarily acting alongside the canonical PI3K/Akt/mTORC‐1 axis (see below for further evidence concerning APP independence from mTORC‐1). 4E‐BP1 is an important node where the activity of different kinases and phosphatases converge to regulate cell growth (She et al, 2010). …”

“…This event is an indication of increased cap‐dependent translation (She et al, 2010 Thoreen et al, 2012). Our data support the idea that APP influences translation primarily by affecting the efficiency of eIF‐4A association with initiation complexes.…”