Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma

Abstract

Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. We have previously reported the discovery of EPZ005678 and EPZ-6438, potent and selective S-adenosyl-methionine-competitive small molecule inhibitors of EZH2. Although both compounds are similar with respect to their mechanism of action and selectivity, EPZ-6438 possesses superior potency and drug-like properties, including good oral bioavailability in animals. Here, we characterize the activity of EPZ-6438 in preclinical models of NHL. EPZ-6438 selectively inhibits intracellular lysine 27 of histone H3 (H3K27) methylation in a concentration-and time-dependent manner in both EZH2 wild-type and mutant lymphoma cells. Inhibition of H3K27 trimethylation (H3K27Me3) leads to selective cell killing of human lymphoma cell lines bearing EZH2 catalytic domain point mutations. Treatment of EZH2-mutant NHL xenograft-bearing mice with EPZ-6438 causes dose-dependent tumor growth inhibition, including complete and sustained tumor regressions with correlative diminution of H3K27Me3 levels in tumors and selected normal tissues. Mice dosed orally with EPZ-6438 for 28 days remained tumor free for up to 63 days after stopping compound treatment in two EZH2-mutant xenograft models. These data confirm the dependency of EZH2-mutant NHL on EZH2 activity and portend the utility of EPZ-6438 as a potential treatment for these genetically defined cancers. Mol Cancer Ther; 13(4); 842-54. Ó2014 AACR.

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

“…S1, demonstrating that dosing is sufficient and tolerated for this mouse strain. In contrast, previous work has shown that tazemetostat induces robust tumor regressions in multiple tumor models bearing EZH2 gain-of-function mutations (30).…”

“…No cell line was passaged for more than 6 months prior to an experiment. Culture of diffuse large B-cell lymphoma cells WSU-DLCL2, SU-DHL-10, Toledo, and OCI-LY19 has been described previously (24,30). KARPAS-422 (ACC 32), OCI-LY7 (ACC 688), SU-DHL-5 (ACC 571), and OCI-LY3 (ACC 761) were obtained from DSMZ (German Collection of Microorganisms and Cell Cultures).…”

“…While previous xenograft studies of mutant EZH2 lymphoma models have demonstrated sensitivity to tazemetostat (30), few studies have been carried out to evaluate response from models of wild-type EZH2. Three wild-type cell line xenograft models were developed to study this in greater depth.…”

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

“…First molecules that directly target EZH2 and compete with the cofactor S-adenosylmethionin (SAM) binding have been described. The inhibitor E7438 has shown efficacy in SMARCB1-mutant Rhabdoid tumors (16) and as well as GSK126 and other reported EZH2 inhibitors (17,18), in EZH2-mutant non-Hodgkin lymphoma (19) where activating mutations are described (20). In addition, effects of EZH2 inhibitors in melanoma (21) (26).…”

Structure of the PRC2 complex and application to drug discovery

“…Several lines of evidence suggest that EZH2 deregulation is an important driver of cancer development and progression and that inactivation of EZH2 may be therapeutically effective in many cancers [4,5,11,12,73,[76][77][78][79][80][81][82][83][84][85][86][87][88][89] . EZH2 is highly expressed in a wide range of cancer types, including lung, breast, colon, prostate, bladder and pancreatic cancer, as well as sarcomas and lymphomas [4,5,11,12,76,77,80,82,83,[85][86][87][88] .…”