PBRM1 is a vulnerability in ARID1A deficient multicellular tumor spheroids

Abstract

ARID1A, a subunit of SWI/SNF, has been shown to play a major role in recruitment of the chromatin remodeler to enhancers for transcriptional regulation. Mutations inARID1A have been found in various cancers, many of which form solid tumors. Recent studies have revealed vulnerabilities in cells lacking ARID1A, specifically ARID1B, an ortholog and mutually exclusive subunit, in 2D cell culture. However, identification of vulnerabilities within SWI/SNF for loss of ARID1A in a multicellular tumor spheroid, that mimic in vivo condition within tumors, has not been explored. Here we show in the absence of ARID1A in a MTS model, ARID1B continues to be a vulnerability but we have identified PBRM1 as a new vulnerability within SWI/SNF. Levels of ARID1B and PBRM1 are elevated on loss of ARID1A. Further, reduction of ARID1B and PBRM1 protein levels, decreases cell survival and reduces induction of several hypoxia regulated genes in ARID1A deficient MTSs. Our studies have identified PBRM1 as a new vulnerability in ARID1a deficient cancers and which provides a new target for therapeutic strategies.