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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI199838

Therapeutic targeting of the eIF4E cap-binding domain reveals control of lineage fate in prostate cancer

Rashmi Mishra,1 Sihyeon Song,1 Dhruv Choradia,1 Dmytro Rudoy,1 Cynthia L. Wladyka,1 Patrick Hoang,1 Jin Yeong Kim,1 Ilsa M. Coleman,1 Sonali Arora,1 Stephanie Dobersch,1 Alexander E. Orellana,1 ChenWei Lin,2 Philip R. Gafken,2 Eva Corey,3 Peter S. Nelson,1 Sita Kugel,1 Haolong Li,1 Arnab Sengupta,4 and Andrew C. Hsieh1

1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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1Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

2Proteomics & Metabolomics Shared Resource, Fred Hutchinson Cancer Center, Seattle, United States of America

3Department of Urology, University of Washington, Seattle, United States of America

4Department of Biological and Environmental Sciences, Georgia College & State University, Milledgeville, United States of America

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Published April 15, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI199838.
Copyright © 2026, Mishra et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 15, 2026 - Version history
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Abstract

Lineage plasticity underscores the resilience of cancer cells in the context of drug treatment. However, lineage fates can also be therapeutically directed. We demonstrate that the eukaryotic initiation factor 4E (eIF4E) cap-binding domain is a critical regulator of lineage plasticity in prostate cancer. Using a first-in-class cap-binding domain inhibitor, we found that plasticity is driven by translational repression of basal keratins through a shared cis-regulatory element enciphered in their 5' untranslated regions (UTRs). Simultaneously this stabilized the androgen receptor (AR) through translational upregulation of the deubiquitinases BAP1 and OTUD3. This lineage program is essential for cell survival and drives a druggable vulnerability. Notably, tumors resistant to AR blockade regained sensitivity upon eIF4E cap-binding domain inhibition, which reprogrammed them toward a luminal state. In castration-resistant prostate cancer (CRPC) patients, elevated eIF4E expression was associated with a basal phenotype, reduced luminal differentiation and accelerated resistance to AR pathway inhibitors (ARPIs). These discoveries uncover a role for the eIF4E cap-binding domain in lineage plasticity and highlight that targeting this domain offers a promising strategy to overcome treatment resistance in prostate cancer.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Supplemental Table 1. HPGTMT_on_LuCaP176_upon_PF07293623vsDMSO.

View Supplemental Table 3. List of Genes with 5′ UTR AGCCWCCAGC motif of HPG-TMT targets_FIMO Analysis

View Supplementary Table 2. RNA-seq of of LuCaP 176 cells treated with and without PF-07293623 for 6 hours.

View Supplemental Table 4. List of cell Lines and mouse models.

View Supplemental Table 5. List of primary antibodies.

View Supplemental Table 6. List of qPCR primers.

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Version history
  • Version 1 (April 15, 2026): In-Press Preview
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