BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature–positive castration-resistant prostate cancer
Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen
Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen
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Research Article Cell biology Genetics Oncology

BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature–positive castration-resistant prostate cancer

Abstract

A subgroup (~20%–30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by 2 GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlated with adverse clinical outcomes to androgen receptor (AR) signaling inhibitor treatment and shorter overall survival. Bromo- and extraterminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, whereas AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers, while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.

Authors

Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M. Schoeps, Holly M. Nguyen, Jennifer L. Conner, Marjorie L. Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R. Pachai, Juan Yan, Nicholas A. Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen

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Figure 1

A high HNF score in CRPC correlates with adverse clinical outcomes.

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A high HNF score in CRPC correlates with adverse clinical outcomes. (A) ...
(A) Patient stratification based on HNF scores in the Alumkal et al. data set (10). Each dot represents 1 patient. The HNF score was calculated as the log2 sum z score of mRNA expression of 11 genes. A sum z score ≥ 12 was annotated as a high HNF score and < 12 as a low HNF score. (B) Enzalutamide response of patient tumors with high and low HNF scores. Statistical significance was determined using Fisher’s exact test. (C) Comparison of HNF scores between enzalutamide nonresponders and responders (top) and GSEA plot of PCa_GI gene signature (bottom) in enzalutamide nonresponders compared with responders. P values determined by unpaired, 2-tailed t test. NES, normalized enrichment score. (D) Patient stratification based on HNF score expression in the SU2C data set. Each dot represents 1 patient. Tumors with a sum z score of ≥ 12 were annotated as expressing a high HNF score; a sum z score of ≤ 0 was a low HNF score; and a value between 0 and 12 was intermediate HNF_score. (E) Kaplan-Meier curve comparing ARSI outcome measures among the 3 groups stratified by HNF scores. P values were determined by log-rank (Mantel-Cox) test. (F) Kaplan-Meier curve comparing overall survival outcomes among the 3 groups stratified by HNF scores. P values were determined by log-rank (Mantel-Cox) test.