Therapeutic targeting of eIF4E cap-binding domain reveals control of lineage fate in prostate cancer [CUT&Run]

Mechanistically, this plasticity is driven by translational repression of basal keratins via cis-regulatory elements in the 5' untranslated regions (UTRs) of their transcripts, alongside promoting androgen receptor (AR) protein stability through the translational upregulation of deubiquitinases BAP1 and OTUD3.

This lineage switch is essential for cell survival and represents a druggable vulnerability. In castration-resistant prostate cancer (CRPC), high eIF4E expression is associated with basal phenotype, reduced luminal differentiation and accelerated resistance to AR pathway inhibitors (ARPIs). Notably, tumors resistant to enzalutamide regain sensitivity upon inhibition of the eIF4E cap-binding domain, which reprograms them toward a luminal state.