# EZH2

Source: https://onco.cc/targets/ezh2/  
OnCo record `ezh2` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

EZH2 is an enzyme that silences genes. The first drug against it treated a rare sarcoma and some lymphomas until it was withdrawn in 2026 for causing second blood cancers.

## Summary

Tazemetostat was approved in epithelioid sarcoma (2020) and EZH2-mutant follicular lymphoma, but Ipsen withdrew it from all markets and indications on 9 March 2026 after the SYMPHONY-1 trial showed excess secondary haematologic malignancies (FDA alert March 2026). EZH2 inhibition continues to be explored (mevrometostat in prostate cancer; SCLC re-sensitisation), now under a safety cloud.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Also known as: PRC2
- Tags: epigenetic
- Symbol: EZH2
- Class: enzyme
- Biology: Catalytic subunit of PRC2, writes H3K27me3.
- Where found: Epithelioid sarcoma (INI1 loss); Follicular lymphoma; Castration-resistant prostate cancer

## Notes

- Prostate cancer: EZH2 and SOX2 are raised in the tumours that lose RB1 and TP53 and change lineage, and EZH2 inhibition restored androgen receptor expression and antiandrogen sensitivity in the mouse models, which is the rationale for the EZH2 inhibitor trials in this disease (Ku 2017).
- Lymphoma, EZH2 gain of function: EZH2 is the catalytic subunit of polycomb repressive complex 2 and writes the H3K27 trimethyl mark. The lymphoma mutations replace a single tyrosine in the SET domain, Tyr641 in the numbering of the original report and Tyr646 in current usage, and they change what the enzyme can do rather than removing it: the mutant converts the di-methyl mark to the tri-methyl mark efficiently while losing the ability to make the first methylation, so a cell carrying one mutant and one wild-type allele piles up H3K27me3 and holds the germinal-centre programme shut. This is the opposite of the loss-of-function EZH2 mutation found in myeloid disease. Frequency: Tyr641 substitutions in 21.7% of germinal-centre diffuse large B-cell lymphomas and 7.2% of follicular lymphomas, and absent from activated B-cell-like cases (Morin 2010). What it changes about treatment: Yes, and it is one of only two genotype-selected drug choices in B-cell lymphoma. Tazemetostat is licensed for relapsed follicular lymphoma, with a higher response rate in the mutant group than in the wild-type group, and it is the reason an EZH2 mutation test is ordered at all.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/EZH2
- FDA alert: Tazverik withdrawal (March 2026): https://www.fda.gov/drugs/drug-alerts-and-statements/fda-alerts-health-care-providers-and-patients-about-increased-risk-new-blood-cancers-tazverik
- Morin et al., Nat Genet 2010: somatic EZH2 Tyr641 mutations in follicular and germinal-centre diffuse large B-cell lymphoma: https://doi.org/10.1038/ng.518

## Connected records

- cancers: [Atypical teratoid/rhabdoid tumour (ATRT)](https://onco.cc/cancers/atrt/), [Chordoma](https://onco.cc/cancers/chordoma/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Diffuse midline glioma, H3 K27-altered (including DIPG)](https://onco.cc/cancers/dipg-dmg/), [Epithelioid sarcoma](https://onco.cc/cancers/epithelioid-sarcoma/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- drugs: [Mevrometostat](https://onco.cc/drugs/mevrometostat/), [Tazemetostat](https://onco.cc/drugs/tazemetostat/), [XNW5004](https://onco.cc/drugs/xnw5004/)
- companies: [ORIC Pharmaceuticals](https://onco.cc/companies/oric-pharmaceuticals/), [Treeline Biosciences](https://onco.cc/companies/treeline-biosciences/)
- pathways: [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [MicroRNAs in cancer](https://onco.cc/pathways/micrornas-in-cancer/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- key papers: [A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications](https://onco.cc/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/), [Genetics and pathogenesis of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/), [Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes](https://onco.cc/key-papers/paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/)
- trials: [MEVPRO-1](https://onco.cc/trials/mevpro-1/), [Tazemetostat with doxorubicin as front-line therapy for advanced epithelioid sarcoma (EZH-301 run-in)](https://onco.cc/trials/tazemetostat-doxorubicin-es/)
- terms: [BAP1 loss](https://onco.cc/terms/bap1-loss/), [Cancer stem cell theory and phenotypic plasticity](https://onco.cc/terms/cancer-stem-cell-theory/), [Cell of origin (GCB vs ABC)](https://onco.cc/terms/cell-of-origin/), [Cell of origin in practice: Hans against expression profiling, and what it changes](https://onco.cc/terms/lymphoma-bio-cell-of-origin-in-practice/), [Epigenetic progenitor theory: cancer without a first mutation](https://onco.cc/terms/epigenetic-progenitor-theory/), [FLIPI, FLIPI2 and POD24 (follicular lymphoma risk)](https://onco.cc/terms/flipi/), [Hallmark (2022): unlocking phenotypic plasticity](https://onco.cc/terms/unlocking-phenotypic-plasticity/), [LymphGen and the genetic clusters of large B-cell lymphoma](https://onco.cc/terms/lymphoma-bio-lymphgen/), [The germinal centre: why lymphoma starts where antibodies are made](https://onco.cc/terms/lymphoma-bio-germinal-centre/)
- biomarkers: [EZH2 gain-of-function mutation (Tyr646, originally Tyr641)](https://onco.cc/biomarkers/ezh2-y646-mutation/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- ideas: [Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain](https://onco.cc/ideas/lymphoma-ev-genetic-subtype-directed-first-line/), [Block the chemical switch that lets cells hide from treatment](https://onco.cc/ideas/idea-bio1-epigenetic-persister-blockade/), [Design drug pairs where resisting one makes you vulnerable to the other](https://onco.cc/ideas/idea-bio1-evolutionary-double-bind/), [Group trials by broken mechanism, not by organ or single mutation](https://onco.cc/ideas/idea-bio2-mechanism-defined-baskets/), [Unmask hidden antigens with a short epigenetic course before immunotherapy](https://onco.cc/ideas/idea-bio2-epigenetic-priming-cold-tumours/)
- technologies: [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/)
- people: [Kristian Helin](https://onco.cc/people/kristian-helin/)
- institutions: [The Wistar Institute](https://onco.cc/institutions/wistar/)

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JSON: https://onco.cc/api/v1/entities/ezh2.json