[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-338211-105":59,"doc-detail-338211-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","parp-1-selectively-impairs-kras-driven-phenotypic-and-molecular-features-in-intrahepatic-cholangiocarcinoma","PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma","","Intrahepatic cholangiocarcinoma (iCCA) is a frequent primary liver cancer with limited treatment options. KRAS mutations are common in iCCA and are linked to poor outcomes, yet PARP-1’s role in cholangiocarcinogenesis is unclear. PARP-1 inhibition was tested in patient-derived and established iCCA models using RNAi, CRISPR/Cas9, and pharmacological approaches, alongside PARP-1 knockout mice. Findings show PARP-1 enhancement and preferential impairment of KRAS-mutant tumor phenotypes via CHK1 signaling.",{"@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/parp-1-selectively-impairs-kras-driven-phenotypic-and-molecular-features-in-intrahepatic-cholangiocarcinoma/338211/",{"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/parp-1-selectively-impairs-kras-driven-phenotypic-and-molecular-features-in-intrahepatic-cholangiocarcinoma/338211.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does this study address in intrahepatic cholangiocarcinoma?","Question",{"text":112,"@type":113},"It addresses limited therapeutic options in iCCA and the unclear contribution of PARP-1 to KRAS-driven cholangiocarcinogenesis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was PARP-1 function tested in KRAS-mutant and non-mutant iCCA?",{"text":117,"@type":113},"PARP-1 inhibition was evaluated in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9, and pharmacological inhibition, and in mice using Parp-1 knockout combined with iCCA induction.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism mediates PARP-1 effects in KRAS-mutant iCCA according to the results?",{"text":121,"@type":113},"The study reports that PARP-1 effects are mediated through CHK1 activation and that CHK1 inhibition reverses PARP-1–mediated effects.","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},338211,1790095578,{"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":44,"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},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Hepatology  \nOriginal research  \nPARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma  \nFriederike L Keggenhoff, 1 Darko Castven,2 Diana Becker, 1 Stojan Stojkovic,2 Jovana Castven,2 Carolin Zimpel,2 Beate K Straub,3,4 Tiemo Gerber,3 Harald Langer,5 Patricia Hähnel,6 Thomas Kindler,6 Jörg Fahrer,7 Colm J O’Rourke,8 Ursula Ehmer,9 Anna Saborowski, 10 Lichun Ma, 11 Xin Wei Wang, 11,12 Timo Gaiser  , 13 Matthias S Matter, 14 Christian Sina, 15 Stefanie Derer  , 15 Ju-Seog Lee  , 16 Stephanie Roessler  , 17 Bernd Kaina, 18 Jesper B Andersen  ,8 Peter R Galle, 1 Jens U Marquardt  2  \n► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/gutjnl-2023-331237](10.1136/gutjnl-2023-331237)) .  \nFor numbered affiliations see end of article.  \nCorrespondence to  \nProfessor Jens U Marquardt; [Jens.Marquardt@uksh.de](Jens.Marquardt@uksh.de)  \nFLK and DC contributed equally.  \nReceived 19 October 2023 Accepted 24 May 2024 Published Online First  \n10 June 2024  \n© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.  \nTo cite: Keggenhoff FL, Castven D, Becker D, et al. Gut 2024;73:1712–1724 .  \nAbsTrACT  \nObjective Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer  \nwith limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose) polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined.  \nDesign PARP-1 inhibition was performed in patientderived and established iCCA cells using RNAi, CRISPR/ Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular features of Kras-driven and Kras-wildtype iCCA. Clinical implications were confirmed in authentic human iCCA.  \nresults PARP-1 was significantly enhanced in KRASmutant human iCCA. PARP-1-based interventions preferentially impaired cell viability and tumourigenicity in human KRAS-mutant cell lines. Consistently, loss of Parp-1 provoked distinct phenotype in Kras/Tp53-induced versus Akt/Nicd-induced iCCA and abolished Kras-dependent cholangiocarcinogenesis. Transcriptome analyses confirmed preferential impairment of DNA damage response pathways and replicative stress response mediated by CHK1 . Consistently, inhibition of CHK1 effectively reversed PARP-1 mediated effects. Finally, Parp-1 depletion induced molecular switch of KRAS-mutant iCCA recapitulating good prognostic human iCCA patients.  \nConclusion Our findings identify the novel prognostic and therapeutic role of PARP-1 in iCCA patients with activation of oncogenic KRAS  signalling.  \nInTrODuCTIOn  \nIntrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer (PLC) with increasing incidence and rising mortality  \n\n| WHAT Is ALrEADY KnOWn On THIs TOPIC |\n| --- |\n| ⇒ PARP-1 is involved in multiple oncogenic pathways and processes, including DNA repair, genomic stability, chromatin modification, energy metabolism and apoptosis. Evidence suggests an association between PARP-1 overexpression and KRAS mutations in various cancers, such as acute myeloid leukaemia and colorectal cancer. However, there is limited information available on the impact of PARP-1 expression on therapeutic response in KRASmutant intrahepatic cholangiocarcinoma (iCCA) .\u003Cbr>WHAT THIs sTuDY ADDs |\n| ⇒ Our results demonstrate that KRASmutant iCCA cells become highly sensitive to PARP-1 depletion and inhibition in vitro while Parp-1 deficient mice show reduced cholangiocarcinogenesis in vivo.\u003Cbr","cbCaicnD1eTo1tDI","https://ap.wps.com/l/cbCaicnD1eTo1tDI","pdf",13689587,13,"English","# Abstract\n## Objective\n## Design\n## Results\n## Conclusion\n# Introduction\n# What is already known on this topic\n# What this study adds\n# How this study might affect research, practice or policy","[{\"question\":\"What problem does this study address in intrahepatic cholangiocarcinoma?\",\"answer\":\"It addresses limited therapeutic options in iCCA and the unclear contribution of PARP-1 to KRAS-driven cholangiocarcinogenesis.\"},{\"question\":\"How was PARP-1 function tested in KRAS-mutant and non-mutant iCCA?\",\"answer\":\"PARP-1 inhibition was evaluated in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9, and pharmacological inhibition, and in mice using Parp-1 knockout combined with iCCA induction.\"},{\"question\":\"What mechanism mediates PARP-1 effects in KRAS-mutant iCCA according to the results?\",\"answer\":\"The study reports that PARP-1 effects are mediated through CHK1 activation and that CHK1 inhibition reverses PARP-1–mediated effects.\"}]","PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma | PDF",1790022543,33]