The eukaryotic translation initiation factor eIF4E is an oncogene elevated in an estimated 30% of cancers. The traditional view is that eIF4E drives proliferation and survival by increasing the translation of a subset of mRNAs encoding proteins involved in these processes. eIF4E also promotes the nuclear cytoplasmic mRNA export of a subset of growth promoting transcripts. This enables eIF4E to elevate the cytoplasmic concentration of these transcripts and thus their protein levels without a priori altering their translation. Indeed, the mRNA export function of eIF4E contributes to its oncogenic potential. eIF4E requires specific mRNA elements and co-factors to act in mRNA export and also modulates the nuclear pore complex to enable this activity. In acute myeloid leukemia (AML), the nuclear localization and mRNA export function of eIF4E is highly elevated. NMR, mass spectrometry and other biophysical studies demonstrate that ribavirin directly binds and inhibits eIF4E. In the first two clinical studies to ever target eIF4E, ribavirin led to molecular targeting of eIF4E activity, and substantial responses including remissions in relapsed and refractory AML patients. Eventually all responding patients relapsed, analysis of patients specimens revealed a novel form of drug resistance: Gli1 inducible drug glucuronidation. Indeed, this form of resistance was also relevant to the standard of care for AML, cytarabine. New clinical studies targeting eIF4E and this form of drug resistance using Gl1i inhibitors are planned.
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