{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T10:16:14Z","timestamp":1778494574198,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,7]]},"group-title":"Cancer Biology","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"National Institutes of Health Intramural Research Programs, National Cancer Institute, Center for Cancer Research","award":["ZIA BC 010547"],"award-info":[{"award-number":["ZIA BC 010547"]}]},{"name":"National Institutes of Health Intramural Research Programs, National Center for Advancing Translational Sciences","award":["ZIA TR 000047"],"award-info":[{"award-number":["ZIA TR 000047"]}]},{"name":"National Institutes of Health, National Cancer Institute","award":["HHSN26120150003I"],"award-info":[{"award-number":["HHSN26120150003I"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>STATEMENT OF SIGNIFICANCE<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.04.722693","type":"posted-content","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T22:25:15Z","timestamp":1778192715000},"source":"Crossref","is-referenced-by-count":0,"title":["Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer"],"prefix":"10.64898","author":[{"given":"Jessica D.","family":"Kindrick","sequence":"first","affiliation":[{"name":"Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 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