Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer

Abstract

The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a valid drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. Focusing on MAK683-sensitive tumors with SMARCB1 or ARID1A loss, we identified a group of PRC2 target genes with high H3K27me3 signal through epigenomic and transcriptomic analysis. Multiple senescence-associated secretory phenotype (SASP) genes, such as GATA4, MMP2/10, ITGA2 and GBP1, are in this group besides previously identified CDKN2A/p16. Upon PRC2 inhibition, the de-repression of SASP genes is detected in multiple sensitive models and contributes to decreased Ki67+, extracellular matrix (ECM) reorganization, senescence associated inflammation and tumor regression even in CDKN2A/p16 knockout tumor. And the combination of PRC2 inhibitor and CDK4/6 inhibitor leads to better effect. The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs.

Cancer-Associated Stromal Fibroblast-Derived Transcriptomes Predict Poor Clinical Outcomes and Immunosuppression in Colon Cancer

“…It has been reported that FBN2 could have excellent diagnostic value for smooth muscle sarcoma and rhabdomyosarcoma [ 70 , 71 ]. Besides, it also has been proved that FBN2 might both have tumor-suppressive effects and is a typical basement membrane marker in several types of cancers [ 72 ]. Previous studies have found that FBN2 harbour cancer-specific promoter methylation in human colorectal cancer [ 73 ].…”

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…Inhibition of EZH2 reduces the repopulation potential of HSPC clones carrying p53 [ 157 ]. Additional mutations in the PRC2 (The methyltransferase Polycomb Repressive Complex 2) Destabilizing PRC2-complex which consists of EZH1, EZH2, SUZ12, and EED subunits, cause cell cycle arrest that overcomes the induction of p53 clonality, and cells exhibit senescence-like phenotypes [ 159 , 160 , 161 ]. In addition, the loss-of-function double mutation of Tp53 and Tet1 (10-11-translocation-1) also induces senescence [ 162 ], illustrating subtle genetic regulation between apoptosis, senescence induction, and clonal proliferation (see Figure 2 ).…”

Structure-Based Design of the Indole-Substituted Triazolopyrimidines as New EED–H3K27me3 Inhibitors for the Treatment of Lymphoma

“…31,32 Particularly, MAK683, a derivative of EED226, has entered phase 2 clinical trials to treat lymphomas. 33 In addition, von Hippel−Lindau (VHL) ligandbased EED-targeted PROTAC degraders have also been documented (Figure 1B). The EED-targeted bivalent chemical degrader UNC6852, via recruitment of VHL, selectively degrades EED, EZH2, and SUZ12; impairs the PRC2 catalytic activity; decreases the H3K27me3 levels; and shows antiproliferation in diffuse large B cell lymphoma (DLBCL) cell lines with EZH2-activating mutations.…”

“…Regulating the PRC2 activity is a promising anticancer therapeutic strategy, and some compounds including small-molecule inhibitors and proteolysis-targeting chimaera (PROTAC) degraders targeting the PRC2 complex have been reported. , To date, several EZH2 inhibitors have entered clinical development, of which tazemetostat has been approved by the FDA to treat epithelioid sarcoma and follicular lymphoma. , Targeting the protein–protein interactions represents a new paradigm to allosterically regulate the protein functions. , In addition to targeting EZH2, targeting the H3K27me3 binding pocket in EED can allosterically regulate the PRC2 methyltransferase activity and thus represents a novel anticancer strategy. − The development of EED inhibitors has been pursued, and some representative EED inhibitors such as EED226, MAK683, A-395, BR-001, EEDi-5285, and EEDi-5273 are shown in Figure A. These EED inhibitors show strong inhibitory activity against EZH2 inhibitor-resistant cells and also exhibit robust regression of lymphoma xenografts. , Particularly, MAK683, a derivative of EED226, has entered phase 2 clinical trials to treat lymphomas . In addition, von Hippel–Lindau (VHL) ligand-based EED-targeted PROTAC degraders have also been documented (Figure B).…”