Evidence map›Paper›PMID 42146671›Full record

ArticlebioRxiv : the preprint server for biology2026

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

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 and 12 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Jessica D KindrickGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Kinjal BhadreshaClinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Xiaohu ZhangDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Erica L BeatsonGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Spencer S GautGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Benjamin C BrimGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Patrick J SignorelliGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Roger DepazGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jessica L HornerClinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Posey S WhiddenClinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
John M ChingClinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Kelli M WilsonDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Savannah WoodDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Crystal McKnightDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Erin BeckDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Carleen Klumpp-ThomasDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Ross LakeLaboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Elijah EdmondsonMolecular Histopathology Lab, Laboratory of Animal Sciences Program, Frederick National Lab for Cancer Research.
Michele CeribelliDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Cindy H ChauGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Craig J ThomasDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
William D FiggGenitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.ORCID 0000-0003-2428-5613

Funding

Drug Development for Prostate Cancer and other Metastatic ProcessesZIABC010547 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI FIGG, WILLIAM DOUGLAS · 2009 to 2025
$10.2M
HTS enabled examination of drug combinationsZIATR000047 · NCATS · NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES · PI THOMAS, CRAIG · 2015 to 2025
$7.1M
Intramural NIH HHS ZIA BC010547Intramural NIH HHS ZIA TR000047
6 · The paper itself

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.

Identifiers

PMID42146671
PMCPMC13174548

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.