The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide

Jaimie S Gray; Sajad A Wani; Shahid Hussain; Phoebe Huang; Debasis Nayak; Mark D Long; Clayton Yates; Steven K Clinton; Chad E Bennet; Christopher C Coss; Moray J Campbell

doi:10.1101/2023.11.15.567282

The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide

bioRxiv [Preprint]. 2023 Nov 17:2023.11.15.567282. doi: 10.1101/2023.11.15.567282.

Authors

Jaimie S Gray^{1

2

3}, Sajad A Wani^{1

3}, Shahid Hussain^{4

5

6}, Phoebe Huang¹, Debasis Nayak¹, Mark D Long⁷, Clayton Yates^{8

9

10}, Steven K Clinton^{2

3}, Chad E Bennet¹¹, Christopher C Coss^{1

3

11}, Moray J Campbell^{1

4

5

6}

Affiliations

¹ College of Pharmacy, Division of Pharmaceutics and Pharmacology; The Ohio State University, Columbus, OH 43210.
² College of Medicine; The Ohio State University, Columbus, OH 43210.
³ Comprehensive Cancer Center; The Ohio State University, Columbus, OH 43210.
⁴ Board of Governors Innovation Center; Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
⁵ Cedars-Sinai Cancer; Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
⁶ Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
⁷ Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.
⁹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
¹⁰ Department of Oncology Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287 USA.
¹¹ Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.

Abstract

We have dissected the role of Estrogen receptor beta (ERβ) in prostate cancer (PCa) with a novel ERβ ligand, OSU-ERb-12. Drug screens revealed additive interactions between OSU-ERB-12 and either epigenetic inhibitors or the androgen receptor antagonist, Enzalutamide (Enza). Clonogenic and cell biolody studies supported the potent additive effects of OSU-ERB-12 (100nM) and Enza (1μM). The cooperative behavior was in PCa cell lines treated with either OSU-ERB-12 plus Enza or combinations involving 17β-estradiol (E2). OSU-ERb-12 plus Enza uniquely impacted the transcriptiome, accessible chromatin, and the AR, MYC and H3K27ac cistromes. This included skewed transcriptional responses including suppression of the androgen and MYC transcriptomes, and repressed MYC protein. OSU-ERb-12 plus Enza uniquely impacted chromatin accessibility at approximately 3000 nucleosome-free sites, enriched at enhancers, enriched for basic Helix-Loop-Helix motifs. CUT&RUN experiments revealed combination treatment targeting of MYC, AR, and H3K27ac again shaping enhancer accessibility. Specifically, it repressed MYC interactions at enhancer regions enriched for bHLH motifs, and overlapped with publicly-available bHLH cistromes. Finally, cistrome-transcriptome analyses identified ~200 genes that distinguished advanced PCa tumors in the SU2C cohort with high androgen and low neuroendocrine scores.

Publication types

Preprint

Grants and funding

P30 CA016058/CA/NCI NIH HHS/United States