epz-6438 and Carcinoma

NUT carcinoma is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT's ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth.. Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827.

Topics: Animals; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Chromatin; Enhancer of Zeste Homolog 2 Protein; Genes, Tumor Suppressor; Histones; Humans; Mice; Neoplasm Recurrence, Local; Nuclear Proteins; Transcription Factors

NUT carcinoma (NC) is one of the most common types of undifferentiated carcinomas affecting young adults with a dismal prognosis. NUT carcinomas often involve chromosomal translocations, leading to the production of BRD4-NUT fusion protein that generates large domains of hyperactive chromatin and activates oncogenic gene expression. Bromodomain and extraterminal domain (BET) bromodomain inhibitors offer a direct means to block BRD4-mediated gene activation but have shown limited clinical efficacy in patients. In this issue of Cancer Research, Huang and colleagues report an unexpected discovery of a synthetic lethal NC dependency on Polycomb repressive complex 2 (PRC2)-mediated gene repression, including EZH2, the catalytic subunit of PRC2. EZH2 is highly expressed in NC patient tumors and a specific inhibitor of its methyltransferase activity, tazemetostat, exhibits potent antitumor cell activity. While the repressed and activated chromatin domains in NC cells are distinct, the resultant gene expression changes exhibit convergent features, including dysregulation of CDKN2A and the E2F-RB1 axis. As a result, combined treatment of NC tumors with tazemetostat and the BET inhibitor mivebresib produces marked antitumor therapeutic synergy in vitro and in vivo, associated with enhanced suppression of RB1 function through convergent remodeling of NC gene expression. This study advances epigenetic cooperativity as a distinct mode of gene expression dysregulation in NC and nominates a compelling combination epigenetic strategy for investigation in clinical trials for patients. See related article by Huang et al., p. 3956.

Topics: Carcinoma; Cell Cycle Proteins; Chromatin; Epigenesis, Genetic; Humans; Nuclear Proteins; Polycomb Repressive Complex 2; Transcription Factors; Young Adult