Metastatic castration-resistant prostate cancer (mCRPC) remains lethal as adaptive resistance to standard-of-care therapy develops, often driven by AR splice variants alongside transcriptional and translational reprogramming. To identify strategies capable of overcoming these mechanisms, we performed an unbiased high-throughput screen of 2,480 mechanistically annotated compounds across advanced prostate cancer models. Exportin-1 (XPO1)-mediated nuclear export emerged as a critical dependency, and matrix-based combination screening uncovered robust synergy between inhibitors of XPO1 and the translation initiation factor EIF4A1. Dual inhibition induced coordinated disruption of oncogenic protein networks, including AR/AR-V7, triggering apoptosis and suppressing cell-cycle and metabolic programs. These effects extended to genetically diverse patient-derived organoids and in vivo xenografts at low doses, approximately 8-fold (Eltanexor) and 12-fold (Zotatifin) below established human single-agent regimens. Together, these findings reveal concurrent control of nuclear export and protein translation as a therapeutic vulnerability in mCRPC, providing a strong rationale for clinical evaluation of XPO1-EIF4A1 co-inhibition to overcome AR-driven resistance.
Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.
bioRxiv : the preprint server for biology. 2026 May 07*** epublish ***
Jessica D Kindrick, Kinjal Bhadresha, Xiaohu Zhang, Erica L Beatson, Spencer S Gaut, Benjamin C Brim, Patrick J Signorelli, Roger Depaz, Jessica L Horner, Posey S Whidden, John M Ching, Kelli M Wilson, Savannah Wood, Crystal McKnight, Erin Beck, Carleen Klumpp-Thomas, Ross Lake, Elijah Edmondson, Michele Ceribelli, Cindy H Chau, Craig J Thomas, William D Figg