Mechanisms and Vulnerabilities of Mutant SWI/SNF Complexes in Cancer

Abstract

Genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in a wide variety of cancers, but the mechanism of cancer formation following SWI/SNF subunit mutation is not known. As a result, improved understanding of how mutation of these subunits promotes oncogenesis could have broad relevance for human cancer therapy. In this dissertation, two distinct lines of investigation were pursued with the common goals of understanding the mechanisms by which SWI/SNF subunit mutation contributes to cancer and identifying vulnerabilities specific to SWI/SNF-mutant cancers. First, a genome-wide screen was used to find specific dependencies conferred by ARID1A mutation, the most frequently mutated subunit of the SWI/SNF complex in cancer. ARID1B was identified as the number one gene specifically essential for the growth of ARID1A-mutant cancers, and ARID1B loss was found to destabilize SWI/SNF and impair cell proliferation in ARID1A-mutant backgrounds. ARID1A and ARID1B were also found to be frequently co-mutated in cancer cell lines and primary samples. Furthermore, these proteins were found to share overlapping roles but also retain unique functions in a cell context dependent manner. Second, DNA methylation was studied as a putative epigenetic mechanism by which mutation of SMARCB1, a core SWI/SNF subunit, leads to genomically stable rhabdoid tumors. Reintroduction of SMARCB1 in rhabdoid tumor cell lines resulted in a decrease of DNA methylation at a subset of upregulated enhancers, identifying DNA methylation as a secondary change following SWI/SNF subunit perturbation. The results from these two distinct lines of study reveal novel vulnerabilities of cancers harboring SWI/SNF mutation and elucidate partial mechanism by which mutation of two unique SWI/SNF subunits contributes to cancer. These findings provide new insight into potential therapeutic opportunities for the wide spectrum of SWI/SNF-mutant cancers.