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EZH2 is identified as a targetable vulnerability in ARID1A-mutant contexts. The study reports tulmimetostat, an orally available clinical-stage EZH2 inhibitor, which shows durable target engagement and comprehensive coverage across ARID1A-mutant tumor models, improves cisplatin response in resistant settings, and generates a peripheral blood gene expression signature that correlates with drug exposure.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/comprehensive-target-engagement-by-the-ezh2-inhibitor-tulmimetostat-allows-for-targeting-of-arid1a-mutant-cancers-research-report/336546/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/comprehensive-target-engagement-by-the-ezh2-inhibitor-tulmimetostat-allows-for-targeting-of-arid1a-mutant-cancers-research-report/336546.png","ImageObject",300,407,{"name":92,"@type":93},"Liam","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does ARID1A mutation play in cancer progression?","Question",{"text":113,"@type":114},"Recurrent ARID1A mutations disrupt chromatin remodeling in cancer cells, creating an altered chromatin state. This can support cancer progression and may create therapeutic dependence on related chromatin regulators.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does tulmimetostat affect ARID1A-mutant tumors?",{"text":118,"@type":114},"Tulmimetostat is an orally available EZH2 inhibitor that achieves comprehensive, durable target engagement. It improves efficacy in multiple ARID1A-mutant tumor models and enhances cisplatin response in chemotherapy-resistant settings.",{"name":120,"@type":111,"acceptedAnswer":121},"How is tulmimetostat target coverage assessed in patients?",{"text":122,"@type":114},"Phase I clinical pharmacokinetic and pharmacodynamic data indicate durable exposure and profound target engagement. A controlled gene expression signature in whole blood from patients correlates with tulmimetostat exposure, serving as a pharmacodynamic marker for PRC2-targeted coverage.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},336546,1790151558,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers  \nPatricia J. Keller1, Elizabeth J. Adams1, Rentian Wu1, Alexandre Ct1, Shilpi Arora1, Nico Cantone1, Rosana Meyer1, Jennifer A. Mertz1, Victor Gehling1, Jike Cui1, Jacob I. Stuckey1, Avinash Khanna1, Feng Zhao1, Zehua Chen1, Ziyang Yu1, Richard T. Cummings1, Mohammed Taimi1, Nehal J. Lakhani2, Drew Rasco3, Martin Gutierrez4, Linda Duska5, Michael Devitt5, Ronda Rippley1, Julian Levell1, Jennifer Truong1, Jing Wang1, Kaiming Sun1, and Patrick Trojer1  \n|  |  | A |  | B | S |  | T | R |  | A |  | C | T |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n|  | Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in\u003Cbr>􀀶 |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  | addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations.\u003Cbr>Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood. |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |\n\nIntroduction  \nCancer genomic alterations in certain chromatin modifier encoding genes result in dysregulation of chromatin regulatory","cbCaiqTIybYfBnp6","https://ap.wps.com/l/cbCaiqTIybYfBnp6","pdf",5310854,17,"English","# Introduction\n## Chromatin modifier mutations in cancer\n## Targeting EZH2 in ARID1A-mutant tumors\n# Study description and findings\n## Tulmimetostat target inhibition and efficacy in models\n## Effects on gene expression and H3K27me3\n## Pharmacokinetics, pharmacodynamics, and blood signature","[{\"question\":\"What role does ARID1A mutation play in cancer progression?\",\"answer\":\"Recurrent ARID1A mutations disrupt chromatin remodeling in cancer cells, creating an altered chromatin state. This can support cancer progression and may create therapeutic dependence on related chromatin regulators.\"},{\"question\":\"How does tulmimetostat affect ARID1A-mutant tumors?\",\"answer\":\"Tulmimetostat is an orally available EZH2 inhibitor that achieves comprehensive, durable target engagement. It improves efficacy in multiple ARID1A-mutant tumor models and enhances cisplatin response in chemotherapy-resistant settings.\"},{\"question\":\"How is tulmimetostat target coverage assessed in patients?\",\"answer\":\"Phase I clinical pharmacokinetic and pharmacodynamic data indicate durable exposure and profound target engagement. A controlled gene expression signature in whole blood from patients correlates with tulmimetostat exposure, serving as a pharmacodynamic marker for PRC2-targeted coverage.\"}]","Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers - Research Report | PDF",1790015554,43]