{"entity":{"id":"paper-ezh2-sarcoma-biochem-pharmacol-2023","kind":"paper","name":"Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors","aka":[],"tldr":"Review on EZH2 in Sarcomas, in Biochemical pharmacology (2023), one of the most cited Europe PMC records with EZH2 in its title.","summary":"Soft tissue sarcomas (STSs) are rare mesechymal malignancies characterized by distintive molecular, histological and clinical features. Many STSs are considered as predominatly epigenetic diseases due to underlying chromatin deregulation. Discovery of deregulated functional antagonism between the chromatin remodeling BRG1/BRM-associated (BAFs) and the histone modifying Polycomb repressor complexes (PRCs) has provided novel actionable targets. In epithelioid sarcoma (ES), extracranial, extrarenal malignant rhabdoid tumors (eMRTs) and synovial sarcoma (SS), the total or partial loss of the BAF core subunit SMARCB1, driven by different alterations, is associated with PRC2 deregulation and dependency on its enzymatic subunit, EZH2. In these SMARCB1-deficient STSs, aberrant EZH2 expression and/or activity emerged as a druggable vulnerability. Although preclinical investigation supported EZH2 targeting as a promising therapeutic option, clinical studies demonstrated a variable response to EZH2 inhibitors. Actually, whereas the clinical benefit recorded in ES patients prompted the FDA approval of the EZH2 inhibitor tazemetostat, the modest and sporadic responses observed in eMRT and SS patients highlighted the need to deepen mechanistic as well as pharmacological investigations to improve drug effectiveness. We summarize the current knowledge of different mechanisms driving SMARCB1 deficiency and EZH2 deregulation in ES, eMRT and SS along with preclinical and clinical studies of EZH2-targeting agents. Possible implication of the PRC2- and enzymatic-independent functions of EZH2 and of its homolog, EZH1, in the response to anti-EZH2 agents will be discussed together with combinatorial strategies under investigation to improve the efficacy of EZH2 targeting in these tumors.\n\nIndexed on Europe PMC as PubMed record 37541451 (DOI 10.1016/j.bcp.2023.115727). Its title names EZH2 and its text names Sarcomas; PubMed types it as a review (Research Support, Non-U.S. Gov't, Review). It was matched automatically to the idea \"Group trials by broken mechanism, not by organ or single mutation\" and no figure has been checked by an editor.","asOf":"2026-09-22","links":[{"label":"Biochem Pharmacol 2023","url":"https://doi.org/10.1016/j.bcp.2023.115727"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/37541451/"},{"label":"Europe PMC","url":"https://europepmc.org/article/MED/37541451"}],"tags":["europepmc-ingest"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Biochemical pharmacology","year":2023,"doi":"10.1016/j.bcp.2023.115727","pmid":"37541451","authors":"Lanzi C, Arrighetti N, Pasquali S, et al.","paperType":"review","findings":[],"whatItMeans":"One of the most cited reviews Europe PMC returns for EZH2 in Sarcomas, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.","caveats":["Matched by EZH2 in the title and Sarcomas in the title or abstract of the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.","A review summarises other studies; the primary reports it cites are the evidence."]},"route":"/key-papers/paper-ezh2-sarcoma-biochem-pharmacol-2023/","neighbours":{"idea":[{"id":"idea-bio2-mechanism-defined-baskets","kind":"idea","name":"Group trials by broken mechanism, not by organ or single mutation","route":"/ideas/idea-bio2-mechanism-defined-baskets/"}]}}