Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer

  • bioRxiv. 2026 May 7:2026.05.04.722693. doi: 10.64898/2026.05.04.722693.
Jessica D Kindrick  1  2 ,  Kinjal Bhadresha  3 ,  Xiaohu Zhang  2 ,  Erica L Beatson  1 ,  Spencer S Gaut  1 ,  Benjamin C Brim  1 ,  Patrick J Signorelli  1 ,  Roger Depaz  1 ,  Jessica L Horner  3 ,  Posey S Whidden  3 ,  John M Ching  3 ,  Kelli M Wilson  2 ,  Savannah Wood  2 ,  Crystal McKnight  2 ,  Erin Beck  2 ,  Carleen Klumpp-Thomas  2 ,  Ross Lake  4 ,  Elijah Edmondson  5 ,  Michele Ceribelli  2 ,  Cindy H Chau  1 ,  Craig J Thomas  2 ,  William D Figg Sr  1  3
Affiliations
  • 1. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • 3. Clinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
  • 4. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5. Molecular Histopathology Lab, Laboratory of Animal Sciences Program, Frederick National Lab for Cancer Research.
PMID: 42146671 DOI: 10.64898/2026.05.04.722693
Abstract

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.

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