[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-333269-105":59,"doc-detail-333269-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","a-synergistic-two-drug-therapy-specifically-targets-a-dna-repair-dysregulation-that-occurs-in-p53-deficient-colorectal-and-pancreatic-cancers","A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers","","Alruwaili and colleagues present a two-drug therapeutic strategy aimed at p53-mutant colorectal and pancreatic cancers by exploiting abnormal DNA repair behavior. p53-mutant cells accumulate DNA breaks when challenged with thymidine analogs through post-replicative repair processes. PARP inhibition markedly amplifies double-strand breaks and cell death triggered by thymidine analogs, while p53 wild-type cells mount p53-dependent cell-cycle inhibition. Trifluorothymidine combined with PARP inhibitors shows synergistic anti-neoplastic activity in p53-mutant cancer models.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-synergistic-two-drug-therapy-specifically-targets-a-dna-repair-dysregulation-that-occurs-in-p53-deficient-colorectal-and-pancreatic-cancers/333269/",{"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/a-synergistic-two-drug-therapy-specifically-targets-a-dna-repair-dysregulation-that-occurs-in-p53-deficient-colorectal-and-pancreatic-cancers/333269.png","ImageObject",300,407,{"name":92,"@type":93},"Lucas Martin","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-12","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What DNA repair abnormality is observed in p53-deficient (p53Mut) cancer cells?","Question",{"text":112,"@type":113},"Thymidine analog challenge reveals a dysregulation in the DNA repair response of p53Mut cells, leading to accumulation of DNA breaks.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does PARP inhibition affect thymidine analog-induced DNA damage in p53Mut cells?",{"text":117,"@type":113},"PARP inhibitors markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells.",{"name":119,"@type":110,"acceptedAnswer":120},"Why do trifluorothymidine and PARP inhibitor combinations show superior anti-neoplastic activity?",{"text":121,"@type":113},"Their combined effects act synergistically against p53Mut cancer models by strengthening thymidine analog-driven DNA damage beyond what either approach achieves alone.","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},333269,1790170896,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},8796095360427,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Article  \nA synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers  \nAuthors  \nMohammed M. Alruwaili,  \nJustin Zonneville, Maricris N. Naranjo, ..., Renuka Iyer, Christos Fountzilas, Andrei V. Bakin  \nCorrespondence  \n[christos.fountzilas@roswellpark.org](christos.fountzilas@roswellpark.org)[ ](christos.fountzilas@roswellpark.org)(C.F.),  \n[andrei.bakin@roswellpark.org](andrei.bakin@roswellpark.org) (A.V.B.)  \nIn brief  \nAlruwaili et al. demonstrate that p53-mutant cancer cells accumulate DNA breaks due to post-replicative removal of thymidine analogs following DNA replication. Inhibition of PARP enhances DNA damage induced by thymidine analogs, leading to cell death. These findings support a two-drug combination strategy to improve outcomes for patients with p53-mutant cancer.  \nd Trifluorothymidine induces DNA breaks in p53-mutant cells via post-replicative repair  \nd PARP inhibitor enhances DNA breaks induced by trifluorothymidine, leading to cell death  \nd Trifluorothymidine and PARP inhibitor act synergistically against p53-mutant cancers  \nAlruwaili et al., 2024, Cell Reports Medicine 5, 101434 March 19, 2024 ª 2024 The Author(s) .  \n[https://doi.org/10.1016/j.xcrm.2024.101434](https://doi.org/10.1016/j.xcrm.2024.101434)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nA synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers  \nMohammed M. Alruwaili,1,2 Justin Zonneville,1 Maricris N. Naranjo,1 Hannah Serio,1 Thomas Melendy,3  \nRobert M. Straubinger,4,5 Bryan Gillard,4 Barbara A. Foster,5 Priyanka Rajan,1 Kristopher Attwood,6 Sarah Chatley,7 Renuka Iyer,7 Christos Fountzilas,7,* and Andrei V. Bakin1,8,*  \n1Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n2Department of Medical Laboratory Technology, College of Applied Medical Science, Northern Border University, Arar City, Saudi Arabia  \n3Department of Microbiology and Immunology, University at Buffalo, Buffalo, NY 14214, USA  \n4Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA  \n5Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n6Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n7Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \n8Lead contact  \n*Correspondence: [christos.fountzilas@roswellpark.org](christos.fountzilas@roswellpark.org) (C.F.), [andrei.bakin@roswellpark.org](andrei.bakin@roswellpark.org) (A.V.B.) [https://doi.org/10.1016/j.xcrm.2024.101434](https://doi.org/10.1016/j.xcrm.2024.101434)  \nSUMMARY  \nThe tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer.  \nINTRODUCTION  \nColorectal adenocarcinoma (CRC) and pancreatic ductal adenocarcinoma (PDAC) are among the leading causes ","cbCaihqk4fAxPGgo","https://ap.wps.com/l/cbCaihqk4fAxPGgo","pdf",6654687,"English","# Summary\n## Therapeutic strategy targeting DNA repair\n## Mechanistic findings and drug synergy","[{\"question\":\"What DNA repair abnormality is observed in p53-deficient (p53Mut) cancer cells?\",\"answer\":\"Thymidine analog challenge reveals a dysregulation in the DNA repair response of p53Mut cells, leading to accumulation of DNA breaks.\"},{\"question\":\"How does PARP inhibition affect thymidine analog-induced DNA damage in p53Mut cells?\",\"answer\":\"PARP inhibitors markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells.\"},{\"question\":\"Why do trifluorothymidine and PARP inhibitor combinations show superior anti-neoplastic activity?\",\"answer\":\"Their combined effects act synergistically against p53Mut cancer models by strengthening thymidine analog-driven DNA damage beyond what either approach achieves alone.\"}]","A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers | PDF",1790001730,48]