Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer.

Abstract

PURPOSE:

The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.

EXPERIMENTAL DESIGN:

We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.

RESULTS:

BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.

CONCLUSIONS:

Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.

• Authors: Steven Kregel, Rohit Malik, Irfan A Asangani, Kari Wilder-Romans, Thekkelnaycke Rajendiran, Lanbo Xiao, Josh N Vo, Tanu Soni, Marcin Cieslik, Ester Fernadez-Salas, Bing Zhou, Xuhong Cao, Corey Speers, Shaomeng Wang, Arul M Chinnaiyan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 13 Pg. 4038-4048 (07 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30918020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• Proteins
• bromodomain and extra-terminal domain protein, human

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression Profiling
• Humans
• Lipid Metabolism
• Male
• Metabolomics (methods)
• Models, Biological
• Neoplasm Metastasis
• Neoplasm Staging
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology, therapy)
• Proteins (metabolism)
• Proteolysis
• Proteomics (methods)
• Xenograft Model Antitumor Assays