https://orcid.org/0000-0002-2852-7280
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ABSTRACT
Introduction
The bromodomain and extraterminal (BET) family of proteins are epigenetic readers of acetylated histones and are critical activators of oncogenic networks across many cancers. Therapeutic targeting of BET proteins has been an attractive area of clinical development for metastatic castration-resistant prostate cancer. In recent years, many structurally diverse BET inhibitors have been discovered and tested. Preclinical studies have demonstrated significant antiproliferative activity of BET inhibitors against prostate cancer. However, their clinical success as monotherapies has been limited by treatment-associated toxicities, primary and acquired drug resistance, and a lack of predictive biomarkers of benefit.
Areas covered
This review provides an overview of advancements in BET inhibitor design, preclinical research, and conclusions from clinical trials in prostate cancer. We speculate on incorporating BET inhibitors into combination regimens with other agents to improve the therapeutic index of BET inhibition in treating prostate cancer.
Expert opinion
The therapeutic potential of BET inhibitors for prostate cancer has been demonstrated in preclinical studies. However, further research is needed to identify biomarkers that can predict sensitivity to BET inhibitors and to develop novel, highly selective inhibitors to reduce toxicities. Finally, BET inhibitors are likely to hold the most clinical potential in combination with other agents.
Article highlights
Bromodomain and extraterminal (BET) proteins are critical readers of acetylated histones that regulate gene expression.
BET proteins play a role in prostate cancer progression through their ability to regulate both the androgen receptor’s transcriptional activity and the expression of several other oncogenes (including c-MYC) that play crucial roles in prostate cancer.
BET proteins play an important role in repairing DNA double-strand breaks, mediating the formation of oncogenic gene fusions, and driving lineage plasticity
BET inhibitors show significant antiproliferative activity against various cancers in preclinical studies.
Despite the compelling preclinical data, BET inhibitors have not met expectations in human clinical trials.
Advancements in developing BET inhibitors are ongoing.
Further research will help to identify biomarkers that can predict sensitivity to BET inhibitors.
Novel combination strategies incorporating BET inhibitors may be required to maximize clinical benefit and reduce toxicity in the treatment of metastatic prostate cancer.
List of abbreviations
| ADT | = | androgen deprivation therapy |
| AML | = | acute myeloid leukemia |
| AR | = | androgen receptor |
| ARE | = | androgen response elements |
| AR-V7 | = | androgen receptor splice variant 7 |
| ATM | = | ataxia-teleangiectasia mutated |
| BCL9 | = | B-cell lymphoma 9 |
| BD | = | bromodomain |
| BET | = | bromodomain and extraterminal protein |
| BRCA | = | breast cancer gene |
| BRD2 | = | bromodomain-containing protein 2 |
| BRD3 | = | bromodomain-containing protein 3 |
| BRD4 | = | bromodomain-containing protein 4 |
| BRDT | = | bromodomain testis-specific protein |
| dBET1 | = | BET degrader 1 |
| dBET6 | = | BET degrader 6 |
| CBP | = | CREB binding protein |
| CDK4 | = | cyclin dependent kinase 4 |
| CD8 | = | cluster of differentiation 8 |
| CI | = | confidence interval |
| CIP | = | CDK interacting protein |
| CREB: | = | cAMP-response element binding protein |
| CTLA4 | = | cytotoxic T-lymphocyte–associated antigen 4 |
| DBD | = | DNA binding domain |
| DSB | = | double-strand breaks |
| DNA | = | deoxyribonucleic acid |
| DNMT | = | DNA methyltransferase |
| DUB3 | = | deubiquitinating enzyme 3 |
| ERG | = | ETS-related gene |
| ERK | = | extracellular signal-regulated kinase |
| ETS | = | erythroblast transformation specific |
| EZH2 | = | enhancer of zeste 2 polycomb repressive complex 2 subunit |
| E2F1 | = | E2 promoter binding factor 1 |
| FOXO1 | = | forkhead box protein O1 |
| FZD2 | = | frizzled class receptor 2 |
| GI: | = | gastrointestinal |
| HDAC | = | histone deacetylase |
| ICI | = | immune checkpoint inhibitor |
| LBD | = | ligand binding domain |
| LEF | = | lymphoid enhancer factor |
| LSD1 | = | Lysine Specific Demethylase 1 |
| mCRPC | = | metastatic castration-resistant prostate cancer |
| MAPK | = | mitogen activated protein kinase |
| MHC | = | major histocompatibility complex |
| MM | = | multiple myeloma |
| mTOR | = | mammalian target of rapamycin |
| NCOR2 | = | nuclear receptor corepressor 2 |
| NEPC | = | neuroendocrine prostate cancer |
| NHL | = | non-Hodgkin lymphoma |
| NMC | = | NUT midline carcinoma |
| NSCLC | = | non-small cell lung cancer |
| PC | = | prostate cancer |
| PDAC | = | pancreatic ductal carcinoma |
| PD-L1 | = | programmed death-ligand 1 |
| PI3K | = | phosphatidylinositol 3-kinase |
| PIP2 | = | phosphatidylinositol-(4,5)-bisphosphonate |
| PIP3 | = | phosphatidylinositol-(3,4,5)-trisphosphate |
| PARP | = | Poly-ADP ribose polymerase |
| PFS | = | progression-free survival |
| PI3K | = | phosphoinositide 3-kinase |
| PROTAC | = | Proteolysis-Targeting Chimera |
| PTEN | = | phosphatase and tensin homolog |
| Rb | = | retinoblastoma |
| RNA | = | ribonucleic acid |
| ROR2 | = | receptor tyrosine kinase-like orphan receptor 2 |
| RYK | = | receptor-like tyrosine kinase |
| rPFS | = | radiographic progression-free survival |
| SCLC | = | small cell lung cancer |
| SPOP | = | speckle-type POZ protein |
| S6K1 | = | ribosomal protein S6 kinase 1 |
| TCF | = | T-cell factor |
| TMPRSS2 | = | transmembrane serine protease 2 |
| TNBC | = | triple-negative breast cancer |
| TOP1 | = | DNA topoisomerase 1 |
| VANGL 1/2 | = | van gogh-like protein 1/2 |
| WAF | = | wild-type p53-activated fragment |
| Wnt | = | Wingless-related integration site |
Declaration of interest
MC Markowski declares consulting fees from Clovis Oncology, Exelixis.
MA Carducci declares honoraria from Acrivon, Astra Zeneca, Sanofi-Genzyme, Pfizer.
ES Antonarakis declares honoraria from, Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas; Pharma, Merck, AstraZeneca, Clovis Oncology, Amgen, Bayer, Blue Earth; Diagnostics, Bristol Myers Squibb/Celgene, Celgene, Constellation; Pharmaceuticals, Curium Pharma, Lilly, Exact Sciences, Foundation Medicine; GlaxoSmithKline, InVitae, ISMAR Health Care, Tempus, Orion, AIkido Pharma. Consulting or Advisory Role: Sanofi, Dendreon, Janssen Biotech, ESSA, Merck; AstraZeneca, Clovis Oncology, Lilly, Bayer, Amgen, Astellas Pharma, Blue Earth; Diagnostics, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals; Curium Pharma, Exact Sciences, Foundation Medicine, GlaxoSmithKline; InVitae, ISMAR Health Care, Medivation, Tempus, Orion, AIkido Pharma. Research funding from Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst); Millennium (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai; Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst); Constellation Pharmaceuticals (Inst), Celgene, Clovis Oncology. Co-inventor of a biomarker technology that has been licensed to Qiagen.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.