Vulnerabilities of mutant SWI/SNF complexes in cancer

Abstract

Cancer genome sequencing efforts have revealed the novel theme that chromatin modifiers are frequently mutated across a wide spectrum of cancers. Mutations in genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are particularly prevalent, occurring in 20% of all human cancers. As these are typically loss-of-function mutations and not directly therapeutically targetable, central goals have been to elucidate mechanism and identify vulnerabilities created by these mutations. Here, we discuss emerging data that these mutations lead to the formation of aberrant residual SWI/SNF complexes that constitute a specific vulnerability and discuss the potential for exploiting these dependencies in SWI/SNF mutant cancers.

Figure 1. SWI/SNF complexes modulate transcription and genes encoding subunits of SWI/SNF complexes are mutated in cancer

SWI/SNF complexes are found in two major subtypes, BAF and PBAF, and are comprised of multiple subunits (top left). SWI/SNF complexes contribute to transcription modulation by mobilizing nucleosomes and by interacting with transcription factors, coactivators, and corepressors on DNA. Subunits found mutated in cancer are denoted by a red star and are described in the table (top right).

Figure 2. Residual SWI/SNF complexes are a vulnerability in cancers containing SWI/SNF subunit mutation

Mutation of a gene encoding a SWI/SNF complex subunit results in the formation of a residual complex that is specifically dependent upon other subunits and essential for the growth of the cancer. Targeting subunits of this residual complex is a newly identified therapeutic opportunity.