The Historic Methyltransferase Ezh2 Catalytic Activity Is Required For Cell Growth In Diffuse Large B-Cell Lymphoma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Lysine methyltransferases and demethylases were identified as transcriptional co-regulators functioning by either preserving particular chromatin methylation states or by controlling placement and removal of histone lysine methylation marks to promote dynamic changes in gene expression. The development of small molecule methyltransferase and demethylase inhibitors provides a novel approach to affect the regulation of transcription, and thus potentially allowing interference with aberrant transcriptional programs as observed, for instance, in cancer. Enhancer of Zeste Homolog 2 (EZH2), the major histone H3 lysine 27 (K27) methyltransferase, is widely implicated in tumor progression. The presence of a recurrent mutation of a single tyrosine residue in the EZH2 catalytic domain in germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and follicular lymphoma suggests that these cancers might be dependent on altered EZH2 molecular function, the mutation facilitating the conversion of an H3K27 di-methylated to a tri-methylated state. Inhibition of the EZH2 catalytic activity will provide a new therapeutic approach to treat human cancers, especially lymphomas carrying activating mutations. Constellation has identified, characterized and optimized potent, selective and reversible EZH2 small molecule inhibitors as well as studied the biological impact of such inhibition. We find that pharmacological inhibition of EZH2 causes selective cell viability defects with cell lines harboring EZH2 mutations being the most sensitive. Our EZH2 inhibitors potently engage the target in vivo and exhibit efficacy in lymphoma xenograft models. Genome-wide mapping of EZH2 and H3K27me3 sites in the absence and presence of the compound revealed that the EZH2 inhibitor caused significant changes to the local chromatin modification landscape, however only a subset of these alterations translated into gene expression changes. The discovery of additional contexts that define sensitivity to EZH2 inhibitors will be discussed. Citation Format: James E. Audia, Patrick Trojer, Shivani Garapaty, Fei Lan, Vidya Balasubramanian, Eric Chan, Charles Hatton, Robert Campbell, Richard Cummings, Emmanuel Normant, Barbara Bryant, Brian Albrecht, Jean Christophe Harmange, Les Dakin, Victor Gehling, Chris Nasveschuk, Rishi Vaswani, Andrew Cook. The histone methyltransferase EZH2 catalytic activity is required for cell growth in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4621. doi:10.1158/1538-7445.AM2013-4621