Targeting the BAF complex in advanced prostate cancer

ABSTRACT

Introduction

The BRG1/BRM associated factors (BAF) complex is a chromatin remodeling SWI/SNF which is mutated in 20% of cancers. This complex has many interchangeable subunits which may have oncogenic or tumor suppressor activity in a context-dependent manner. The BAF complex is mutated in 35–50% of metastatic prostate cancer (PC); however, its role in advanced disease is unclear. This review attempts to consolidate current knowledge of the BAF complex in PC and explore potential therapeutic approaches.

Areas covered

This review covers the known roles of some BAF subunits, their alterations, and the models which best explain their mechanisms in driving PC. Following this, the authors provide their expert perspective on how this complex could be targeted in the future with a personalized medicine approach.

Expert opinion

Personalized medicine would allow for patient stratification to exploit synthetic lethal strategies in targeting a mutated BAF complex as shown experimentally in other cancers. BAF dependency can also be targeted in patients stratified for other molecular markers such as BRG1 targeting in phosphatase and tensin homolog (PTEN) deficient PC.

KEYWORDS:

• Prostate
• cancer
• ARID1A
• BAF
• SWI/SNF

Article highlights

• 60–70% of cases of metastatic prostate cancer have some alteration in the BAF complex.

• Elevated BRG1 expression and reduced BRM expression often characterize advanced disease.

• The BAF complex functions as a co-activator of the androgen receptor and ERG, two common oncogenic proteins in prostate cancer.

• Mutations in the BAF complex could be therapeutically targeted in prostate cancer by exploiting various synthetically lethal interactions.

• A personalised medicine approach which can screen patients for BAF alterations could allow for therapeutic intervention in patients with metastatic prostate cancer.

Declaration of interest

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.

Additional information

Funding

The authors have been funded by Cancer Research UK through a Clinician Scientist Fellowship (19661).