EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

Abstract

In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

“…15,[19][20][21][22][23][24] Notably, its molecular or pharmacological inhibition leads to the reversal of the malignant phenotype. [24][25][26][27][28][29] Collectively, these findings demonstrate a role of EZH2 as a potential prognostic marker and therapeutic target in cancer. We and others have recently reported that (i) as compared with the normal myoblasts and muscle tissues EZH2 is markedly overexpressed in RMS 30,31 and (ii) EZH2 downregulation in vitro leads to myogenic-like differentiation of an embryonal RMS cell line.…”

“…26,27,29 In the attempt to evaluate the effect of pharmacologic inhibition of EZH2, we have used DZNep, which has been already shown to induce FBXO32 expression in cancer cells 25,28,40,66 in parallel with an EZH2 catalytic inhibitor, MC1945. 33,34 Both pharmacological treatments phenocopied the effects of genetic inhibition of EZH2 in vitro enhancing the apoptotic rate of fusion-positive alveolar RMS cells, upregulating FBXO32 and downregulating Myogenin.…”

Au cœur d’une complexité biologique

“…Les molécules GSK126 et EI1 sont actives à la fois sur les deux formes d'EZH2. Elles inhibent de façon efficace la croissance de lignées cellulaires issues de lymphomes dans lesquelles la protéine EZH2 est mutée [41,42]. Une étude de phase I utilisant la molécule GSK126 a été lancée en avril 2014 chez des patients atteints de lymphomes B. Enfin, une autre étude clinique de phase I portant sur la molécule CPI-1205 dont la structure moléculaire n'a pas encore été dévoilée, a été initiée en 2015 chez des patients atteints de lymphomes B.…”

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] . Correspondingly, overexpression of EZH2 often correlates with advanced stages of human cancer progression and poor prognosis [4,12,76] .…”

“…Since 2010, multiple cancer genome-wide studies have reveal ed that the function of the PRC2 complex and H3K27 methylation are widely associated with tumorigenesis [4,5,12,76,77] . 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] .…”