Therapeutic targeting of the eIF4E cap-binding domain reveals control of lineage fate in prostate cancer
Rashmi Mishra, Sihyeon Song, Dhruv Choradia, Dmytro Rudoy, Cynthia L. Wladyka, Patrick Hoang, Jin Yeong Kim, Ilsa M. Coleman, Sonali Arora, Stephanie Dobersch, Alexander E. Orellana, Chenwei Lin, Philip R. Gafken, Eva Corey, Peter S. Nelson, Sita Kugel, Haolong Li, Arnab Sengupta, Andrew C. Hsieh
Rashmi Mishra, Sihyeon Song, Dhruv Choradia, Dmytro Rudoy, Cynthia L. Wladyka, Patrick Hoang, Jin Yeong Kim, Ilsa M. Coleman, Sonali Arora, Stephanie Dobersch, Alexander E. Orellana, Chenwei Lin, Philip R. Gafken, Eva Corey, Peter S. Nelson, Sita Kugel, Haolong Li, Arnab Sengupta, Andrew C. Hsieh
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Research Article Cell biology Oncology

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

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 patients with castration-resistant prostate cancer (CRPC), 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.

Authors

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

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Figure 4

Basal keratins are translationally controlled and required for cell survival.

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Basal keratins are translationally controlled and required for cell surv...
(A and B) Cell-free SHAPE reactivity of the 5’ UTR of KRT5 from LuCaP 176 cells showing (A) base pairing probability and (B) Secondary structure. (C) KRT5 5′ UTR luciferase assay with stem-loop mutant (Δ41–69), normalized to luciferase mRNA, n = 11 or more. (D) Consensus motif identified within basal keratin 5’ UTRs by MEME Stream. (E) KRT5 5′ UTR luciferase assay with motif mutant (Δ6–15), normalized to luciferase mRNA, n = 8 or more. (F and G) Pooled keratin (siKRT pool) or nontarget control (siNT) knockdown, n = 3, showing (F), keratin protein expression (left) and growth curves (right), as well as (G) caspase-3 activity over time. (H–J) Individual keratin knockdown (siKRTs), n = 3, showing (H) keratin protein expression (I), growth curves, and (J) caspase-3 activity over time. Plots represent mean ± SEM. Significance was determined by 1-way ANOVA with Šidák’s multiple comparisons test in C, E; by one way ANOVA with Dunnett’s multiple comparisons test in G, I, and J; by Unpaired 2-tailed Student’s t test in F. *P < 0.05; **P < 0.01; ****P < 0.0001.