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 7

Combination efficacy of enzalutamide and pelabresib in AR-positive CRPC PDX models.

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Combination efficacy of enzalutamide and pelabresib in AR-positive CRPC ...
(A) Treatment response of LuCaP 70CR PDX in SCID mice when treated with vehicle (0.5% methylcellulose/0.2% Tween-80 in sterile water), enzalutamide (50 mg/kg), pelabresib (30 mg/kg), or enzalutamide and pelabresib. Enzalutamide and pelabresib were oral gavaged once and twice a day, respectively (n = 5 for all treatments). Treatment was started when tumors reached a volume of approximately 100 mm3. Fold change in growth rate over day 0 (start of treatment) is shown. Data are mean ± SEM. P values were determined from a 2-tailed unpaired t test. (B) Immunoblots of 3 representative tumor explants obtained at the end of the experiment shown in A. (C) qRT-PCR analysis of HNF1A, MUC13, TMPRSS2, and KLK3 mRNA levels in tumors harvested at the end of the study. n = 3 for each treatment condition. (D) Treatment response of LuCaP 35CR PDX in SCID mice when treated with vehicle, enzalutamide, pelabresib, or enzalutamide and pelabresib. Treatment conditions were the same as described in A (n = 3 for all treatments). Fold change in growth rate over day 0 (start of treatment) is shown. Data are mean ± SEM. P values were determined from a 2-tailed unpaired t test. (E) Immunoblots of 2 representative tumors obtained at the end of the study shown in D. (F) Left panel shows HNF score modulation in LuCaP 35CR tumors treated with different drugs, as shown in D. The HNF score was calculated using RNA-Seq gene expression generated from explanted tumors at the end of the study. The right panel shows modulation of AR signaling using the AR score. P values were determined from a 2-tailed unpaired t test, n = 3. (G) Treatment response of LuCaP 77CR PDX in SCID mice when treated with vehicle, enzalutamide, pelabresib, or enzalutamide and pelabresib. Treatment conditions were same as described in A (n = 3 for all treatments). Fold change in growth rate over day 0 (start of treatment) is shown. Data are mean ± SEM. P values were determined from a 2-tailed unpaired t test. (H) Immunoblots of 3 representative tumors obtained at the end of the study shown in G. (I) HNF score (left) and AR score (right) modulation in LuCaP 77CR tumors treated with different drugs as shown in G. (J) Treatment response of LuCaP 49, LuCaP 145.2, and LuCaP 93 PDXs in SCID mice when treated with vehicle, enzalutamide, pelabresib or enzalutamide and pelabresib. Treatment conditions were same as described in A. n = 3 for each treatment condition in each PDX line. P values were determined from a 2-tailed unpaired t test (n = 2).