Targeting the Bromodomain of BRG-1/BRM Subunit of the SWI/SNF Complex Increases the Anticancer Activity of Temozolomide in Glioblastoma.

Chuanhe Yang,Duane D Miller,Michelle M Sims,Yinan Wang,Lawrence M Pfeffer,Yali He

doi:10.3390/ph14090904

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.

Highlights

We showed that BRG1 is essential for maintaining the stem cell-like identity of GBM cancer stem cells (GSCs) [11], and BRG1 knockdown in GSCs and in GBM cell lines increases chemosensitivity to the standard-of-care DNA alkylating agent
Mutation and deletion of BRG1/SMARCA4 have been shown to contribute to a range of human malignancies [10,18], suggesting that the SWI/SNF complex acts as a tumor suppressor in these cancers
Recent evidence showed that the SWI/SNF may play a pro-tumorigenic role in other cancers [9,11,12]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Gliomas are the most common primary intracranial neoplasms in adults and a leading cause of cancer-related morbidity and mortality in the United States [1]. While grade I glioma is the least malignant brain tumor, grade IV glioma (GBM, glioblastoma) is the most aggressive and the deadliest brain tumor. Surgical resection of GBM remains the primary treatment modality, combined with adjuvant chemotherapy temozolomide (TMZ)

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