Abstract A hallmark of therapy resistance in advanced castration-resistant prostate cancer (CRPC) is the transition between lineage states from androgen receptor (AR) -dependent to AR-independent phenotypes. Elucidating the mechanisms underlying this lineage plasticity is crucial, as these transitions may represent druggable processes that could be leveraged to resensitize prostate cancer to AR pathway inhibitors (ARPIs) or prevent resistance altogether. Here, we investigated how mRNA translation regulates lineage plasticity and contributes to therapy resistance in prostate cancer. Using nascent proteome mass spectrometry (HPG-TMT), we demonstrate that basal-to-luminal lineage plasticity in prostate epithelium is regulated by the eIF4E cap-binding domain. Mechanistically, inhibition of this domain represses translational of basal keratins via cis-regulatory elements in the 5' untranslated regions (UTRs) of their transcripts, while enhancing AR protein stability through the translational upregulation of the deubiquitinases BAP1 and OTUD3. This coordinated translational reprogramming drives a basal-to-luminal lineage switch essential for cell survival and represents a druggable vulnerability. Clinically, elevated eIF4E expression in CRPC is associated with basal phenotype, reduced luminal differentiation and accelerated resistance to ARPIs. Notably, tumors resistant to enzalutamide regain sensitivity upon inhibition of the eIF4E cap-binding domain, which reprograms them toward a luminal state. These findings identify a novel oncogenic role of the eIF4E cap-binding domain in regulating lineage plasticity and therapy resistance, highlighting its inhibition as a promising strategy to overcome treatment resistance in CRPC. Citation Format: Rashmi Mishra, Sihyeon Song, Dhruv Choradia, Dmytro Rudoy, Cindy L. Wladyka, Patrick Hoang, Jin Yeong kim, Ilsa Coleman, Sonali Arora, Alexander Orellana, ChenWei Lin, Philip Gafken, Eva Corey, Peter Nelson, Haolong Li, Arnab Sengupta, Andrew C. Hsieh. Therapeutic targeting of eIF4E cap-binding domain reveals control of lineage fate in prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR032.
Mishra et al. (Tue,) studied this question.