BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations

ABSTRACT

Introduction: The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR).

Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review.

Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

KEYWORDS:

• Bromodomain
• epigenetics
• prostate cancer
• drug combinations
• BET

Article highlights

• Bromodomain and Extra-Terminal (BET) family of proteins are key readers of acetylated histones that regulate gene expression.

• Clinical development of BET protein inhibitors is ongoing for use in multiple malignancies, including prostrate cancer.

• BRD4 associates with the androgen receptor, potentially serving as an important target of BETi in prostate cancer.

• Novel combination strategies with BETi may be required to maximize clinical benefit in the treatment of metastatic prostate cancer.

This box summarizes key points contained in the article.

Acknowledgments

The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Declaration of Interest

The authors are supported by a National Institutes of Health Grant P30 CA006973 (E. S. Antonarakis), and the Prostate Cancer Foundation (E. S. Antonarakis, M. C. Markowski). They are also partially supported by an ASCO/CCF Young Investigator Award (M. C. Markowski).

E. S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation and ESSA; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Aragon, Genentech, Novartis and Tokai; and he is the co-inventor of a biomarker technology that has been licensed to Tokai and Qiagen. The other 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Funding

This paper was not funded.