Therapeutic targeting of eIF4E cap-binding domain reveals control of lineage fate in prostate cancer

We demonstrate mRNA translation controls basal to luminal lineage plasticity of prostate epithelium through eIF4E cap-binding domain. 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. These discoveries uncover a novel oncogenic role of the eIF4E cap-binding domain in lineage plasticity and therapy resistance and suggest that inhibition of this domain offers a promising strategy to overcome treatment resistance in prostate cancer.