Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma

• Published in: PloS one Vol. 11; no. 7; p. e0158888
• Main Authors: Kawano, Satoshi, Grassian, Alexandra R, Tsuda, Masumi, Knutson, Sarah K, Warholic, Natalie M, Kuznetsov, Galina, Xu, Shanqin, Xiao, Yonghong, Pollock, Roy M, Smith, Jesse S, Kuntz, Kevin K, Ribich, Scott, Minoshima, Yukinori, Matsui, Junji, Copeland, Robert A, Tanaka, Shinya, Keilhack, Heike
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-07-2016; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Bioavailability; Biology and Life Sciences; Cancer; Catalysis; Cell death; Cell Line, Tumor; Chromatin remodeling; Chromosomes; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Enzymatic activity; Fusion protein; Gene expression; Genetic aspects; Histone H3; Homeostasis; Humans; Inhibition; Lysine; Medical prognosis; Medicine and Health Sciences; Metastasis; Methyltransferase; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology; Polycomb group proteins; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Proteins; Research and Analysis Methods; Sarcoma; Sarcoma, Synovial - drug therapy; Sarcoma, Synovial - genetics; Sarcoma, Synovial - metabolism; SMARCB1 Protein - genetics; SMARCB1 Protein - metabolism; Substrates; Sucrose; Sugar; SWI/SNF complex; Synovial sarcoma; Transcription; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Japan; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158888

The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2) methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1) has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.