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

Abstract

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.

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

“…These preclinical data support the hypothesis that rhabdoid tumors are dependent on PRC2 activity, which is dysregulated in SMARCB1-deficient tumors; this leads to the aberrant repression of polycomb target genes, such as those involved in differentiation and tumor suppression. Similarly, we and others have recently shown that mutation of another SWI/SNF member, SS18, in synovial sarcoma, also results in a dependence on EZH2 activity (4,14,15).…”

“…EZH2 is amplified, overexpressed, or mutated in multiple cancer types, most notably follicular lymphoma (FL) and germinal center diffuse large B-cell Lymphoma (DLBCL). We and others have shown that pharmacologic inhibition of EZH2 can block proliferation and survival in a subset of cancer cell lines, supporting its function as an oncogene (1)(2)(3)(4)(5)(6)(7). In addition to posttranslational modifications of chromatin, gene transcription is also regulated by the ATP-dependent remodeling of chromatin structure.…”

Enhancer of zeste homologue 2 (EZH2) expression in synovial sarcomas as a promising indicator of prognosis

“…An excessive expression of EZH2 is found in various carcinomas, lymphomas, and soft tissue sarcomas, and growing evidence suggests that this overexpression correlates with the aggressiveness and poor clinical outcome of such tumors [13][14][15][16][17][18][19][20][21][22]. However, few studies have investigated the expression of EZH2 in SS [23][24][25]. The aim of this study was to investigate the relationship between the EZH2 expression as evaluated by immunohistochemistry and known prognostic indicators in SS.…”

Role of Molecular Profiling in Soft Tissue Sarcoma

“…56 Recent in vivo and xenograft studies have supported the theory that EZH2-mediated activity of PRC2 may be an attractive therapeutic target, demonstrating inhibition of cell growth and migration in synovial sarcoma lines to EZH2 inhibition. 57,58 Clinical trials have now begun, and preliminary data for tazemetostat, a potent and selective EZH2 inhibitor, has shown guarded promise.…”