ATRT-02. THERAPEUTIC TARGETING OF EZH2 AND BET BRD4 IN AT/RT. (23rd April 2019)

• Record Type: Journal Article
• Authors: Zhang, Ali; Piunti, Andrea; Ozark, Patrick; He, Xingyao; Katagi, Hiroaki; Sasaki, Takahiro; Laurie, Kathryn; Goldman, Stewart; Zou, Lihua; Shilatifard, Ali; Hashizume, Rintaro
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii63
• Page End: ii63
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.001
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Atypical teratoid/rhabdoid tumors (AT/RTs) are lethal childhood cancers and defined by inactivation of the SMARCB1 tumor suppressor gene encoding a chromatin remodeling complex which suppresses activity of EZH2 methyltransferase. The absence of SMARCB1 protein promotes increased EZH2 activity, results in increased methylation of histone H3 lysine 27 (H3K27), which is generally associated with transcriptional repression. H3K27 can also be acetylated, which requires bromo- and extra-terminal domain (BET) protein activity to activate transcription. Recent genome-wide ChIP-sequence analyses identified high occupancy of H3K27ac in association with BET bromodomain-containing protein 4 (BRD4) at super-enhancer elements in AT/RT. The aberrant activity of EZH2 and BRD4 histone modifiers is of fundamental importance to the occurrence and biology of AT/RT and actionable targets for treating AT/RT. We tested the effects of targeting inhibition of EZH2 and BRD4 in AT/RT. BRD4 inhibitor JQ1 induced dose-dependent growth inhibition of AT/RT cells with decreased expression of H3K27ac, and combination treatment of EZH2 inhibitor (GSK126) and JQ1 resulted in further suppressed the cell growth and cell invasion relative to either monotherapy. RNA sequence analysis showed differentially expressed genes in response to each treatment and slightly overlap genes associated with JQ1 and GSK126 treatment. We treated the mice with GSK-126 and JQ1 for 3 weeks. Combination therapy suppressed the tumor growth and prolonged animal survival in compared to monotherapy in the mice with intracranial AT/RT xenografts. Collectively, these findings suggest that therapeutic combination of EZH2 and BRD4 inhibitor provides a rational epigenetic targeted therapy for AT/RT.