[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-360009-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-360009-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","parg-inhibition-in-atm-deficient-prostate-cancer-from-mechanistic-discovery-to-therapeutic-potential","PARG inhibition in ATM-deficient prostate cancer: from mechanistic discovery to therapeutic potential","","ATM deficiency is frequently detected in castration-resistant prostate cancer (CRPC), yet actionable therapeutic vulnerabilities linked to this genetic change remain unclear. This study used unbiased small-molecule screening to uncover synthetic lethal strategies selectively lethal to ATM-deficient prostate cancer cells. Results show PARG inhibition causes persistent PARylation, severe replication stress, checkpoint activation, DNA double-strand break accumulation, and cell death in vitro and suppresses ATM-deficient xenograft tumor growth in vivo.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/parg-inhibition-in-atm-deficient-prostate-cancer-from-mechanistic-discovery-to-therapeutic-potential/360009/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/parg-inhibition-in-atm-deficient-prostate-cancer-from-mechanistic-discovery-to-therapeutic-potential/360009.png","ImageObject",300,407,{"name":42,"@type":43},"Melati","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What was the main goal of this study?","Question",{"text":63,"@type":64},"To identify synthetic lethal strategies that selectively target ATM-deficient prostate cancer cells and clarify the underlying mechanisms and therapeutic potential of those strategies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does PARG inhibition affect ATM-deficient prostate cancer cells?",{"text":68,"@type":64},"PARG inhibition induces persistent PARylation in ATM-deficient cells, leading to severe replication stress, checkpoint activation, accumulation of DNA double-strand breaks, and ultimately cell death.",{"name":70,"@type":61,"acceptedAnswer":71},"What evidence supports in vivo therapeutic potential?",{"text":72,"@type":64},"In vivo experiments using ATM-deficient xenograft tumor models showed that PARG inhibition significantly suppressed tumor growth.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},360009,1790193148,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":55,"slug":125},"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145},962085570644,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Zhou et al. Journal of Translational Medicine (2026) 24:648  \n[https://doi.org/10.1186/s12967-026-08208-9](https://doi.org/10.1186/s12967-026-08208-9)  \nJournal of Translational Medicine  \nRESEARCH Open Access  \nPARG inhibition in ATM-deficient prostate cancer: from mechanistic discovery to therapeutic potential  \nXuan Zhou1,2†, Chunyu Guo1†, Zhiguo Fan1†, Yihaoyun Lou1†, Zhiying Yue2, Weidong Xu1*†, Zhixiang Xin1*† and Shancheng Ren 1*†  \nAbstract  \nBackground ATM deficiency is frequently observed in castration-resistant prostate cancer (CRPC) . However, effective therapeutic vulnerabilities associated with this genetic alteration remain poorly defined. This study aimed to identify synthetic lethal strategies that selectively target ATM-deficient prostate cancer cells.  \nMethods An unbiased small-molecule compound screening was performed to identify agents exhibiting selective cytotoxicity in ATM-deficient prostate cancer cells. Candidate vulnerabilities were validated across multiple prostate cancer cell lines with genetic depletion or restoration of ATM. Mechanistic studies were conducted using molecular and biochemical assays to assess DNA damage, replication stress, and PARylation dynamics. In vivo efficacy was evaluated using ATM-deficient xenograft tumor models.  \nResults ATM-deficient prostate cancer cells exhibited marked sensitivity to pharmacological inhibition of poly (ADPribose) glycohydrolase (PARG) using with PDD00017273, an effect that was consistently observed across multiple cell lines and partially restored by ATM re-expression. Mechanistically, PARG inhibition induced persistent PARylation in ATM-deficient cells, not via canonical DNA double-strand break signaling, but via misincorporated ribonucleotides processed by topoisomerase 1 during DNA replication. This replication-associated PARylation resulted in severe replication stress, checkpoint activation, and accumulation of DNA double-strand breaks, ultimately leading to cell death. This cytotoxic mechanism is distinct from classical PAR-dependent cell death pathways, including NAD⁺  \n\n| †Xuan Zhou, Chunyu Guo, Zhiguo Fan and Yihaoyun Lou contributed equally to this work. |\n| --- |\n| †Weidong Xu, Zhixiang Xin and Shancheng Ren jointly surpervised the study and served as corresponding authers. Zhixiang Xin acted as the lead contact for this study and took the leading role in study conception and project coordination. |\n\n*Correspondence: Weidong Xu [ayxwd@qq.com](ayxwd@qq.com)[ ](ayxwd@qq.com)Zhixiang Xin [xiaoxin973@hotmail.com](xiaoxin973@hotmail.com)[ ](xiaoxin973@hotmail.com)Shancheng Ren [renshancheng@gmail.com](renshancheng@gmail.com)  \nFull list of author information is available at the end of the article  \nBackground  \nDeleterious mutations in DNA damage response (DDR) genes are common in advanced prostate cancer (PCa) and they can be inherited or somatically acquired [1]. BRCA2 and ATM are the two most commonly mutated genes [2]. Although PARP inhibitors (PARPi) such asolaparib (OLA) and rucaparib (RUC), are the standard therapy for patients with BRCA1/2 mutations, the response rate to PARPi in patients with ATM mutations is relatively low [3–5].  \nATM is a Ser/Thr kinase that plays a central role in therepair of DNA double strand-breaks (DSB) [6, 7]. When  \n© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line","cbCair9ECn9zW07s","https://ap.wps.com/l/cbCair9ECn9zW07s","pdf",13330961,14,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Keywords\n# Background (DNA damage response and PARP therapy context)\n# Methods (screening and mechanistic validation)\n# Results (mechanism and in vivo efficacy)","[{\"question\":\"What was the main goal of this study?\",\"answer\":\"To identify synthetic lethal strategies that selectively target ATM-deficient prostate cancer cells and clarify the underlying mechanisms and therapeutic potential of those strategies.\"},{\"question\":\"How does PARG inhibition affect ATM-deficient prostate cancer cells?\",\"answer\":\"PARG inhibition induces persistent PARylation in ATM-deficient cells, leading to severe replication stress, checkpoint activation, accumulation of DNA double-strand breaks, and ultimately cell death.\"},{\"question\":\"What evidence supports in vivo therapeutic potential?\",\"answer\":\"In vivo experiments using ATM-deficient xenograft tumor models showed that PARG inhibition significantly suppressed tumor growth.\"}]","PARG inhibition in ATM-deficient prostate cancer: from mechanistic discovery to therapeutic potential | PDF",1790138499,35]