Targeting the Bromodomain of BRG-1/BRM Subunit of the SWI/SNF Complex Increases the Anticancer Activity of Temozolomide in Glioblastoma
Chuanhe Yang, Yinan Wang, Michelle Sims, Yali He, Duane D. Miller, Lawrence M. Pfeffer
Abstract
Glioblastoma (GBM) is a deadly and incurable brain cancer with limited therapeutic options. PFI-3 is a small-molecule bromodomain (BRD) inhibitor of the BRM/BRG1 subunits of the SWI/SNF chromatin remodeling complex. The objective of this study is to determine the efficacy of PFI-3 as a potential GBM therapy. We report that PFI-3 binds to these BRDs when expressed in GBM cells. PFI-3 markedly enhanced the antiproliferative and cell death-inducing effects of temozolomide (TMZ) in TMZ-sensitive GBM cells as well as overcame the chemoresistance of highly TMZ-resistant GBM cells. PFI-3 also altered gene expression in GBM and enhanced the basal and interferon-induced expression of a subset of interferon-responsive genes. Besides the effects of PFI-3 on GBM cells in vitro, we found that PFI-3 markedly potentiated the anticancer effect of TMZ in an intracranial GBM animal model, resulting in a marked increase in survival of animals bearing GBM tumors. Taken together, we identified the BRG1 and BRM subunits of SWI/SNF as novel targets in GBM and revealed the therapeutic potential of applying small molecule inhibitors of SWI/SNF to improve the clinical outcome in GBM using standard-of-care chemotherapy.