Emerging EZH2 Inhibitors and Their Application in Lymphoma

Abstract

Activating mutations and overexpression of EZH2 are found in non-Hodgkin lymphoma (NHL). As a result, several EZH2 inhibitors have been developed and entered clinical investigation. Tazemetostat, first-in-class EZH2 inhibitor, demonstrated enhanced clinical activity in mutant follicular lymphoma and diffuse large B cell lymphoma. With the early activity noted by tazemetostat in B cell lymphomas, the role of EZH2 inhibition in NHL is becoming more evident. This can be leveraged in future rationale combinations to enhance the activity of EZH2 inhibitors.

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

“…Transcription is repressed at least in part by the PRC2 complex, identified recently in a genetic analysis of MHC-I low tumor biopsies (Ennishi et al, 2019). EZH2 Y641 mutations, common in DLBCL, are considered to be hyperactivating (Yap et al, 2011) and are the target for EZH2 inhibitors aimed at starving mutant EZH2 tumors of PRC2 activity in the clinic (Kim and Roberts, 2016;Lue and Amengual, 2018).…”

“…EZH2 is the catalytic core of the PRC2 complex, a general transcriptional repressor involved in methylating K27 of histone H3; small molecule inhibitors (EZH2i) are already being pursued in clinical trials to treat a variety of malignancies (e.g., GSK126 and tazemetostat) (Italiano et al, 2018;Lue and Amengual, 2018).…”

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

“…In addition, missense EZH2 point mutations were also identified in a few Burkitt lymphoma cases with functions not fully determined [48]. Frequencies of EZH2 mutations in different malignant contexts have been summarized before [37,49].…”

The EZ-riding NK/T-cell lymphoma

“…9 Nevertheless, it was the discovery of gain-of-function mutations in B-cell lymphomas, mainly found in those of germinal center origin such as follicular lymphoma and a majority of diffuse large B-cell lymphomas, which led to the development of several EZH inhibitors. 7,8 Li et al now describe an additional role of EZH2 in extranodal NKTL. Previous work from the same group described an alternative pathway whereby JAK3mediated phosphorylation of EZH2 results in decreased methylation of histone H3 on Lys27 (H3K27).…”

“…The role of EZH2 and EZH1 in different tumors is undoubtedly multifaceted with aberrancies involving gain-of-function mutations, loss-of-function mutations, and protein overexpression. 8 Remarkably, in B-cell lymphomas, wild-type EZH2 must be present for gain-of-function mutations to exhibit a survival benefit-a unique phenomenon among human cancers. 9 Nevertheless, it was the discovery of gain-of-function mutations in B-cell lymphomas, mainly found in those of germinal center origin such as follicular lymphoma and a majority of diffuse large B-cell lymphomas, which led to the development of several EZH inhibitors.…”