PRC2 loss impairs small cell lung cancer tumorigenesis and enhances sensitivity to G9a/GLP inhibition

PRC2 loss impairs small cell lung cancer tumorigenesis and enhances sensitivity to G9a/GLP inhibition | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article PRC2 loss impairs small cell lung cancer tumorigenesis and enhances sensitivity to G9a/GLP inhibition Maarten van Lohuizen, Jawahar Kopparam, Gayathri Chandrasekaran, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5952196/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Effective targeted therapies for small cell lung cancer (SCLC) remain a significant challenge. Targeting the epigenome to overcome immune evasion and chemoresistance represents a promising strategy to improve treatment outcomes. In this study, we explored the role of Polycomb repressive complex 2 (PRC2), a key transcriptional repressor, by dissecting its structural and enzymatic functions. Conditional deletion of Eed, a core structural component of PRC2, prevented tumor formation in an autochthonous SCLC model. In contrast, enzymatic inhibition of EZH2 had no impact on tumor growth but significantly altered the PRC2 interactome, unveiling novel targets for drug development. Since EZH2 inhibitors are already clinically approved for other cancers, we conducted a focused combination drug screen to enhance their therapeutic potential in SCLC. Our findings revealed that prolonged EZH2 inhibition sensitized neuroendocrine cancer cells to G9a/GLP inhibition. Transcriptomic analysis revealed that the drug combination triggered an oxidative stress response by modulating the expression of cellular oxidases, an effect that could be reversed by antioxidant treatment. These results underscore the critical role of PRC2’s structural functions in SCLC and identify promising drug combinations to enhance the efficacy of EZH2 inhibitors. Biological sciences/Cancer/Lung cancer/Small-cell lung cancer Biological sciences/Cancer/Cancer therapy/Targeted therapies Small cell lung cancer EED targeted therapy EZH2 combination therapy preclinical models Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable2Drugsynergyscreen.xlsx Drug Synergy screen SupplementaryTable3Proximitylabellingassay.xlsx Proximity labelling assay Cite Share Download PDF Status: Published Journal Publication published 21 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5952196","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":414917620,"identity":"9365e94f-b704-47ba-8ee0-48bf9ecb29ce","order_by":0,"name":"Maarten van 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