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EZH2 Inhibitor Efficacy in Non-Hodgkin’s Lymphoma Does Not Require Suppression of H3K27 Monomethylation

2014; Elsevier BV; Volume: 21; Issue: 11 Linguagem: Inglês

10.1016/j.chembiol.2014.09.017

1879-1301

William D. Bradley, Shilpi Arora, Jennifer Busby, Srividya Balasubramanian, Victor Gehling, Christopher G. Nasveschuk, Rishi G. Vaswani, Chih-Chi Yuan, Charlie Hatton, Feng Zhao, Kaylyn E. Williamson, Priyadarshini Iyer, Jacqui Méndez, Robert M. Campbell, Nico Cantone, Shivani Garapaty-Rao, James E. Audia, Andrew S. Cook, Les A. Dakin, Brian K. Albrecht, Jean-Christophe Harmange, Danette L. Daniels, Richard Cummings, Barbara M. Bryant, Emmanuel Normant, Patrick Trojer,

Lymphoma Diagnosis and Treatment

The histone lysine methyltransferase (MT) Enhancer of Zeste Homolog 2 (EZH2) is considered an oncogenic driver in a subset of germinal center B-cell-like diffuse large B cell lymphoma (GCB-DLBCL) and follicular lymphoma due to the presence of recurrent, monoallelic mutations in the EZH2 catalytic domain. These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations. Here we report the identification of highly potent and selective EZH2 small molecule inhibitors, their validation by a cellular thermal shift assay, application across a large cell panel representing various non-Hodgkin's lymphoma (NHL) subtypes, and their efficacy in EZH2mutant-containing GCB-DLBCL xenograft models. Surprisingly, our EZH2 inhibitors selectively affect the turnover of trimethylated, but not monomethylated histone H3 lysine 27 at pharmacologically relevant doses. Importantly, we find that these inhibitors are broadly efficacious also in NHL models with wild-type EZH2.