Attacking a Nexus of the Oncogenic Circuitry by Reversing Aberrant eIF4F-Mediated Translation

Notwithstanding their genetic complexity, different cancers share a core group of perturbed pathways converging upon a few regulatory nodes that link the intracellular-signaling network with the basic metabolic machinery. The clear implication of this view for cancer therapy is that instead of targeting individual genetic alterations one by one, the next generation of cancer therapeutics will target critical hubs in the cancer network. One such hub is the translation-initiation complex eIF4F, which integrates several cancer-related pathways into a self-amplifying signaling system. When hyperactivated by apical oncogenic signals, the eIF4F-driven translational apparatus selectively switches the translational repertoire of a cell toward malignancy. This central integrative role of pathologically activated eIF4F has motivated the development of small-molecule inhibitors to correct its function. A genome-wide, systems-level means to objectively evaluate the pharmacologic response to therapeutics targeting eIF4F remains an unmet challenge. Mol Cancer Ther; 11(5); 1051-61. (C) 2012 AACR.