[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-372110-105":59,"doc-detail-372110-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","early-tolerance-and-late-persistence-as-alternative-drug-responses-in-cancer","Early tolerance and late persistence as alternative drug responses in cancer","","Bacteria survive antibiotic challenge through resistance, persistence, or tolerance, yet drug-induced tolerance in cancer remained unclear. The study demonstrates that human cancer cells develop a tolerant state upon exposure to standard chemotherapy regimens, driven by widespread autophagy activation and coordinated DNA damage repair pathway induction. With prolonged exposure, tolerant responses transition into persistence as DNA repair becomes fully reversed, mediated by PINK1-dependent mitophagy.",{"@graph":69,"@context":122},[70,84,105],{"@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/early-tolerance-and-late-persistence-as-alternative-drug-responses-in-cancer/372110/",{"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/early-tolerance-and-late-persistence-as-alternative-drug-responses-in-cancer/372110.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What distinguishes tolerance from persistence in survival under treatment?","Question",{"text":112,"@type":113},"Tolerance delays reduction of survivors after exposure and plateaus even at high drug concentrations. Persistence is reflected by biphasic time-kill curves, where the majority is eliminated faster while a minority persists.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do cancer cells respond when exposed to commonly used chemotherapy regimens?",{"text":117,"@type":113},"Cancer cells elicit a tolerant response under chemotherapy exposure, supported by pervasive autophagy activation and comprehensive DNA damage repair pathway activation.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links early tolerance to later persistence in cancer cells?",{"text":121,"@type":113},"After prolonged drug exposure, the tolerant response evolves into persistence with increased DNA damage repair reversed entirely. PINK1-driven mitophagy reduces DNA repair through cytoplasmic relocalization of HNF4A, limiting transcriptional activation of DNA repair genes.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},372110,1790722287,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Article [https://doi.org/10.1038/s41467-024-54728-7](https://doi.org/10.1038/s41467-024-54728-7)  \nEarly tolerance and late persistence as alternative drug responses in cancer  \nReceived: 11 April 2024  \n\n| Accepted: 20 November 2024 |\n| --- |\n| |\n| Check for updates |\n\nSimona Punzi 1,2 , Davide Cittaro 3, Guido Gatti 1,2, Gemma Crupi 1, Oronza A. Botrugno 1, Antonino Alex Cartalemi 1,2, Alon Gutfreund 4, Caterina Oneto 3, Valentina Giansanti 3, Chiara Battistini 5,  \nGiovanni Santacatterina6, Lucrezia Patruno7, Ilaria Villanti2, Martina Palumbo1, Daniel J. Laverty8, Francesca Giannese 3, Alex Graudenzi 7,  \nGiulio Caravagna 6, Marco Antoniotti 7, Zachary Nagel 8, Ugo Cavallaro 5, Luisa Lanfrancone 9, Timothy A. Yap 10, Giulio Draetta 11, Nathalie Balaban4 & Giovanni Tonon 1,2,3   \nBacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization ofthe cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of firstline, adjuvant treatments and debulking in advanced cancers.  \nAntibiotic treatment failures could emerge from the acquisition of resistance mutations but may also arise from two alternative mechanisms including tolerance and persistence, described as early as 19441. Resistance is an inherited trait acquired by bacteria strains through gene transfer or mutations in the resistome2. It is assessed by the minimum inhibitory concentration (MIC), whereby resistant  \nstrains are able to grow at higher MIC3. In tolerance, the bacteria population withstands transient exposure to high antibiotic concentrations otherwise lethal, with no changes in MIC and weakly dependency on the drug concentration administered. This property of tolerant cells is reflected in the time-kill curve, which shows a monophasic delay in reducing the fraction of survivors when compared with  \n1Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 2Università Vita-Salute San Raffaele, Milan, Italy. 3Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy. 4The Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem, Israel. 5Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy. 6Cancer Data Science Laboratory, Department of Mathematics and Geosciences, University of Trieste, Trieste, Italy. 7Department of Informatics, Systems and Communication of the University of Milan-Bicocca, Milan, Italy. 8Harvard Chan School of Public Health, Boston, MA, USA. 9Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy. 10Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 11Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston, Houston, TX, USA. e-mail: [punzi.simona@hsr.it](punzi.simona@hsr.it); [tonon.giovanni@hsr.it](tonon.giovanni@hsr.it)  \nsusceptible bacteria. Importantly, the time-kill curves reach a plateau, even with very high drug concentrations, implying that the frac","cbCaifLIMRkd7yb3","https://ap.wps.com/l/cbCaifLIMRkd7yb3","pdf",3301891,18,"English","# Key Concepts\n## Alternative bacterial survival mechanisms\n## Drug-induced tolerance in cancer\n# Experimental Findings\n## Tolerant response to chemotherapy regimens\n## Transition from tolerance to persistence\n# Mechanistic Insight\n## PINK1/mitophagy regulation of DNA repair\n## Impact on DNA repair gene activation\n# Conclusion\n## Implications for standard-of-care therapy","[{\"question\":\"What distinguishes tolerance from persistence in survival under treatment?\",\"answer\":\"Tolerance delays reduction of survivors after exposure and plateaus even at high drug concentrations. Persistence is reflected by biphasic time-kill curves, where the majority is eliminated faster while a minority persists.\"},{\"question\":\"How do cancer cells respond when exposed to commonly used chemotherapy regimens?\",\"answer\":\"Cancer cells elicit a tolerant response under chemotherapy exposure, supported by pervasive autophagy activation and comprehensive DNA damage repair pathway activation.\"},{\"question\":\"What mechanism links early tolerance to later persistence in cancer cells?\",\"answer\":\"After prolonged drug exposure, the tolerant response evolves into persistence with increased DNA damage repair reversed entirely. PINK1-driven mitophagy reduces DNA repair through cytoplasmic relocalization of HNF4A, limiting transcriptional activation of DNA repair genes.\"}]","Early tolerance and late persistence as alternative drug responses in cancer | PDF",1790193727,45]