Remodeling the cancer epigenome: mutations in the SWI/SNF complex offer new therapeutic opportunities

ABSTRACT

Introduction: Cancer genome sequencing studies have discovered mutations in members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex in nearly 25% of human cancers. The SWI/SNF complex, first discovered in S. cerevisiae, shows strong conservation from yeast to Drosophila to mammals, contains approximately 10–12 subunits and regulates nucleosome positioning through the energy generated by its ATPase subunits. The unexpected finding of frequent mutations in the complex has fueled studies to identify the mechanisms that drive tumor development and the accompanying therapeutic vulnerabilities.

Areas covered: In the review, we focus upon the potential roles different SWI/SNF subunit mutations play in human oncogenesis, their common and unique mechanisms of transformation and the potential for translating these mechanisms into targeted therapies for SWI/SNF-mutant tumors.

Expert opinion: We currently have limited insights into how mutations in different SWI/SNF subunits drive the development of human tumors. Because the SWI/SNF complex participates in a broad range of normal cellular functions, defining specific oncogenic pathways has proved difficult. In addition, therapeutic options for SWI/SNF-mutant cancers have mainly evolved from high-throughput screens of cell lines with mutations in different subunits. Future studies should follow a more coherent plan to pinpoint common vulnerabilities among these tumors.

Trial registration: ClinicalTrials.gov identifier: NCT02601937.

Trial registration: ClinicalTrials.gov identifier: NCT02601950.

Trial registration: ClinicalTrials.gov identifier: NCT03213665.

Trial registration: ClinicalTrials.gov identifier: NCT02059265.

KEYWORDS:

• Cancer
• chromatin remodeling
• SWI/SNF complex
• epigenetics

Article highlights

• Mutations in subunits of the SWI/SNF complex appear in nearly 25% of all human cancers. Many of these tumors behave aggressively with little to no long-term survival. Importantly, some of these tumors possess only a mutation in one SWI/SNF subunit along with little evidence of genomic instability. Therefore, these tumors may represent true ‘epigenetically driven’ cancers.

• The SWI/SNF complex regulates nucleosome positioning throughout the human epigenome through an energy-driven mechanism. Because of this central role in controlling chromatin organization, mutations in the complex can disrupt the regulation of many cellular processes such as proliferation, programmed cell death, and differentiation as well as normal development.

• Because of its broad regulatory roles, studies have identified multiple mechanisms underlying the development of SWI/SNF-mutant tumors including changes in enhancer and super-enhancer sites, altered interactions with key histone modifications, aberrant regulation of the RB and TP53 tumor suppressor pathways and changes in interactions with non-coding RNAs.

• Identification of targeted therapies for SWI/SNF-mutant cancers is in its infancy. However, a notable new class of drugs inhibits the EZH2 histone methyltransferase, a synthetic lethality in a subset of cancers with loss of expression of specific SWI/SNF subunits. Other studies have implicated existing tyrosine kinase inhibitors and immune checkpoint inhibitors as effective on SWI/SNF-mutant tumors. However, the efforts to identify new and effective treatments for these tumors would benefit from a unified approach of seeking common therapeutic vulnerabilities among the mutations in different subunits.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institute of Health. Grant to BE Weissman: CA195670. Grant to T Walhart: CA217824. Grant to V Nguyen: ES007126