[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-376664-105":59,"doc-detail-376664-en":131},{"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":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","the-role-of-wnt-pathway-mutations-in-cancer-development-overview-of-therapeutic-options","The Role of WNT Pathway Mutations in Cancer Development - Overview of Therapeutic Options","","Mutations in the canonical WNT-signalling pathway are established drivers in multiple cancers, making mutation-level and tumour-dependence assessment critical for new therapies. This review distinguishes ligand-dependent mechanisms, where RNF43 or RSPO mutations still require exogenous WNT ligands, from ligand-independent mechanisms, driven by cytoplasmic alterations such as APC and CTNNB1 that activate signalling without ligands. It summarizes predominant driving mutations and evaluates current therapeutic interventions, then proposes a new downstream strategy targeting translation machinery.",{"@graph":69,"@context":123},[70,84,106],{"@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/the-role-of-wnt-pathway-mutations-in-cancer-development-overview-of-therapeutic-options/376664/",{"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/the-role-of-wnt-pathway-mutations-in-cancer-development-overview-of-therapeutic-options/376664.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the key therapeutic relevance of WNT pathway mutations in cancer?","Question",{"text":113,"@type":114},"The review emphasizes that therapy development depends on understanding which cancers are driven by WNT activation and where the mutations occur within the pathway, because dependence on WNT ligands differs by mutation location.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do ligand-dependent and ligand-independent WNT pathway mutations differ?",{"text":118,"@type":114},"Ligand-dependent cases include RNF43 or RSPO mutations that still require exogenous WNT ligands. Ligand-independent cases involve cytoplasmic segment mutations such as APC and CTNNB1 that activate WNT signalling even without WNT ligands.",{"name":120,"@type":111,"acceptedAnswer":121},"What downstream process is linked to β-catenin-mediated gene expression?",{"text":122,"@type":114},"Canonical WNT activation culminates in transcriptional changes driven by β-catenin-mediated transcription, with β-catenin controlled by its cellular location and the destruction complex.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},376664,1790366946,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"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":31},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","cells  \nReview  \nThe Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options  \nWibke Groenewald , Anders H. Lund * and David Michael Gay *  \nCitation: Groenewald, W.; Lund, A.H.; Gay, D.M. The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options. Cells 2023, 12, 990. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells12070990  \nAcademic Editors: Anitha K. Shenoy and Liya Pi  \nReceived: 27 February 2023  \nRevised: 21 March 2023  \nAccepted: 23 March 2023  \nPublished: 24 March 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nBiotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark  \n* Correspondence: [anders.lund@bric.ku.dk](anders.lund@bric.ku.dk) (A.H.L.); [david.gay@bric.ku.dk](david.gay@bric.ku.dk) (D.M.G.)  \nAbstract: It is well established that mutations in the canonical WNT-signalling pathway play a major role in various cancers. Critical to developing new therapeutic strategies is understanding which cancers are driven by WNT pathway activation and at what level these mutations occur within the pathway. Some cancers harbour mutations in genes whose protein products operate at the receptor level of the WNT pathway. For instance, tumours with RNF43 or RSPO mutations, still require exogenous WNT ligands to drive WNT signalling (ligand-dependent mutations) . Conversely, mutations within the cytoplasmic segment of the Wnt pathway, such as inAPC and CTNNB1, lead to constitutive WNT pathway activation even in the absence of WNT ligands (ligand-independent) . Here, we review the predominant driving mutations found in cancer that lead to WNT pathway activation, as well as explore some of the therapeutic interventions currently available against tumours harbouring either ligand-dependent or ligand-independent mutations. Finally, we discuss a potentially new therapeutic avenue by targeting the translational apparatus downstream from WNT signalling.  \nKeywords: WNT; APC; 􀀌-catenin; ligand-dependent; colon cancer; endometrial cancer  \n1. Introduction  \nWNT signalling is one of the most evolutionarily conserved signalling pathways and plays a critical role in many biological processes, including embryonic development, cell proliferation, self-renewal, and cellular differentiation. The first genes involved in the Wnt pathway were discovered in the 1980s. Firstly, the wingless (wg) gene was discovered as a critical regulator of segment polarity in Drosophila [1] . Soon after, the Int-1 oncogene was discovered to be activated in virally-induced breast tumours [2] . Int-1 was subsequently shown to be the mammalian homolog of wg, thereby being the first identification of the crossover of a developmental pathway with cancer [3] .  \nWg/Int-1 was shown to encode a secreted protein—known as WNT ligands, which are secreted in both an autocrine and paracrine fashion. To date, 19 WNT ligands have been identified [4] . These WNT ligands are approximately 40kDa lipid-modified glycoproteins that are palmitoylated by Porcupine (PORCN) [5] ahead of their transportation and secretion by the WNT Ligand Secretion Mediator (WLS) [6] . WNT ligands interact with one of ten Frizzled (FZD) receptors and an associated co-receptor, such as lipoprotein receptor-related proteins 5 and 6 (LRP5/6) [7] . Upon activation, FZDs recruit Dishevelled (DVL) to the cell membrane, which, in turn, can mediate downstream signalling [4] . It is important to note that WNT signalling is divided into canonical and noncanonical WNT signalling pathways [8] . Noncanonical WNT signalling results in ","cbCaitgON9NgfMnR","https://ap.wps.com/l/cbCaitgON9NgfMnR","pdf",2747689,"English","# Introduction\n## Overview of WNT signalling and its roles\n## Canonical versus noncanonical WNT pathways\n# Mechanistic basis of β-catenin activation\n## WNT ligand production and receptor activation\n## Destruction complex regulation in the absence of WNT","[{\"question\":\"What is the key therapeutic relevance of WNT pathway mutations in cancer?\",\"answer\":\"The review emphasizes that therapy development depends on understanding which cancers are driven by WNT activation and where the mutations occur within the pathway, because dependence on WNT ligands differs by mutation location.\"},{\"question\":\"How do ligand-dependent and ligand-independent WNT pathway mutations differ?\",\"answer\":\"Ligand-dependent cases include RNF43 or RSPO mutations that still require exogenous WNT ligands. Ligand-independent cases involve cytoplasmic segment mutations such as APC and CTNNB1 that activate WNT signalling even without WNT ligands.\"},{\"question\":\"What downstream process is linked to β-catenin-mediated gene expression?\",\"answer\":\"Canonical WNT activation culminates in transcriptional changes driven by β-catenin-mediated transcription, with β-catenin controlled by its cellular location and the destruction complex.\"}]","The Role of WNT Pathway Mutations in Cancer Development - Overview of Therapeutic Options | PDF",1790220513]