Targeting EZH2 with tazemetostat

Abstract

Enhancer of zeste homolog 2 (EZH2) is a subunit of the chromatin remodelling polycomb repressive complex 2. EZH2 is a histone methyltransferase and trimethylates histone H3 lysine 27 (H3K27). EZH2 activation contributes to epigenetic transcriptional silencing because H3K27 methylation is a repressive histone modification. 1 Viré E Brenner C Deplus R et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006; 439: 871-874 Crossref PubMed Scopus (1723) Google Scholar Physiologically, EZH2 activity is high in stem or progenitor cells, in which EZH2 represses genes associated with cell cycle arrest and promotes self-renewal. However, in differentiated cells EZH2 activity is opposed by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex, which promotes terminal differentiation and regulates self-renewal. 2 Weissman B Knudsen KE Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer. Cancer Res. 2009; 69: 8223-8230 Crossref PubMed Scopus (91) Google Scholar Results from several preclinical studies showed that aberrant activation of EZH2 or loss-of-function mutations in the SWI/SNF complex appear to be associated with oncogenesis in various human cancers. The EZH2 activating mutation has been identified in 22% of patients with follicular lymphoma and germinal centre B-cell like subtype of diffuse large B-cell lymphoma. 3 McCabe MT Ott HM Ganji G et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492: 108-112 Crossref PubMed Scopus (1343) Google Scholar Loss-of-function mutations in the SWI/SNF complex, such as mutations of INI1 and SMARCA4, are observed in tumours, such as malignant rhabdoid tumours, epithelioid sarcoma, and malignant rhabdoid tumour of the ovary. 2 Weissman B Knudsen KE Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer. Cancer Res. 2009; 69: 8223-8230 Crossref PubMed Scopus (91) Google Scholar Therefore, EZH2 is regarded as a novel therapeutic target for B-cell non-Hodgkin's lymphoma and selected solid tumours. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 studyTazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. Full-Text PDF