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 1

Inhibition of the eIF4E cap-binding domain suppresses advanced prostate cancer growth.

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Inhibition of the eIF4E cap-binding domain suppresses advanced prostate ...
(A) Schematic showing mechanism of action of clinical and preclinical mRNA translation modulators: 2BAct, DN9058, eFT508, eFT226, HHT, and PF-07293623. (B) Preclinical pharmacological screen on LuCaP cell lines. (C) Heatmap showing fold change in growth of LuCaP cells treated with DMSO (vehicle) or translation activators or inhibitors. n = 3 or more. (D) Cell growth curves of LuCaP 35CS, LuCaP 35CR, and LuCaP 176 cells treated with DMSO or PF-07293623, normalized to vehicle. (E) Chemical structure of PF-07293623. (F) Caspase-3 activity over time in LuCaP 176 cells treated with DMSO or PF-07293623 (100 nM) treatment. n = 4. In controls, Staurosporin was used to induce apoptosis and C3 inhibitor was used to inhibit apoptosis. (G) Representative immunoblots (top) and quantification (bottom) of cleaved caspase 3 in LuCaP 176 cells treated with DMSO or PF07293623 (100 nM, 72 hours), n = 6. (H) Heatmap showing fold change in growth of PC3, DU145, LNCaP, 22Rv1, VCaP, and PREC cells treated with DMSO or PF-07293623 (100 nM), n = 3. (I) Cell growth of GFP+ cells expressing vector or eIF4E-GFP constructs treated with DMSO or PF-07293623 (100 nM, 72 hours). (J) Luminal and basal features of LuCaP PDX models. (K and L) LuCaP PDX tumor growth curve (left) and end tumor volumes (right) for (K), LuCaP 35CS PDX treated with vehicle (n = 6), PF07293623 (n = 7), and (L) LuCaP 176 PDX treated with vehicle (n = 6) or PF07293623 (n = 8). Plots represent mean ± SEM. Significance was determined by 1-way ANOVA with Dunnett’s multiple comparisons test in D, F; by Unpaired 2-tailed Student’s t test in G, I, K, and L. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.