title: EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation.
abstract: 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.
authors.forename: William D
authors.initials: WD
authors.lastname: Bradley
authors.forename: Shilpi
authors.initials: S
authors.lastname: Arora
authors.forename: Jennifer
authors.initials: J
authors.lastname: Busby
authors.forename: Srividya
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Victor S
authors.initials: VS
authors.lastname: Gehling
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Nasveschuk
authors.forename: Rishi G
authors.initials: RG
authors.lastname: Vaswani
authors.forename: Chih-Chi
authors.initials: CC
authors.lastname: Yuan
authors.forename: Charlie
authors.initials: C
authors.lastname: Hatton
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Kaylyn E
authors.initials: KE
authors.lastname: Williamson
authors.forename: Priyadarshini
authors.initials: P
authors.lastname: Iyer
authors.forename: Jacqui
authors.initials: J
authors.lastname: Méndez
authors.forename: Robert
authors.initials: R
authors.lastname: Campbell
authors.forename: Nico
authors.initials: N
authors.lastname: Cantone
authors.forename: Shivani
authors.initials: S
authors.lastname: Garapaty-Rao
authors.forename: James E
authors.initials: JE
authors.lastname: Audia
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cook
authors.forename: Les A
authors.initials: LA
authors.lastname: Dakin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Harmange
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bryant
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.forename: Patrick
authors.initials: P
authors.lastname: Trojer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010455:Peptides / Q000032:analysis; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D010455:Peptides; D054852:Small Molecule Libraries; D063151:Polycomb Repressive Complex 2