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Lack of effective medical therapies forces repeated surgeries to control tumour burden. CYLD loss drives growth, and CCS tumours show increased canonical NF-κB and Wnt signalling. This study investigated NF-κB signalling in CCS tumours and keratinocytes to identify druggable targets.",{"@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/targeting-noncanonical-nuclear-factor-kappa-b-signalling-in-cyld-cutaneous-syndrome-by-selective-inhibition-of-ib-kinase-alpha/354183/",{"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/targeting-noncanonical-nuclear-factor-kappa-b-signalling-in-cyld-cutaneous-syndrome-by-selective-inhibition-of-ib-kinase-alpha/354183.png","ImageObject",300,407,{"name":92,"@type":93},"Cipher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What problem does this study address in CYLD cutaneous syndrome (CCS)?","Question",{"text":113,"@type":114},"CCS patients develop many progressively growing skin tumours after puberty and currently have no medical therapies, requiring repeated surgeries to manage tumour burden.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which signalling pathway alteration is the study focused on?",{"text":118,"@type":114},"The study investigates noncanonical nuclear factor kappa B (NF-κB) signalling in CCS tumour cells and tumour keratinocytes, beyond previously reported canonical NF-κB activity.",{"name":120,"@type":111,"acceptedAnswer":121},"What is the key drug target identified, and what effect was observed?",{"text":122,"@type":114},"IκB kinase alpha (IKKα) was identified as a candidate target. A selective IKKα inhibitor (SU1644) reduced tumour spheroid viability in patient-derived CCS tumour models.","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},354183,1790174662,{"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":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":41},687208528416,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","British Journal of Dermatology, 2026, 194, 1130–1141 [https://doi.org/10.1093/bjd/ljag044](https://doi.org/10.1093/bjd/ljag044)  \n[Published: 4 March 2026](Published: 4 March 2026)  \nTranslational research  \nTargeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha  \nKirsty Hodgson,1 Joseph Inns,1 Gary Reynolds,2,3 Emily Stephenson,2 Andrew Paul,4 Naomi Sinclair,1 Giacomo Berretta,4 Christopher Lawson,4 Andrew Michael Frey,2 Iglika Ivanova,2 Eva Adam,5,6 Christopher J Lord,7 Simon Cockell,2 Jonathan Coxhead,2 Nikoletta Nagy,5,6 David Adams,8  \nMarta Szell,5,6 Matthias Trost,2 Muzlifah Haniffa,2,8,9 Simon P Mackay,4 Neil Perkins2 and Neil Rajan1,9  \n1Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK  \n2 Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK  \n3Centre for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA  \n4Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK  \n5 Department of Medical Genetics, University of Szeged, Szeged, Hungary  \n6 HUN-REN-SZTE Functional Clinical Genetics Research Group, Szeged, Hungary  \n7The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK  \n8Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK  \n9 Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Correspondence: Neil Rajan. Email: [neil. rajan@newcastle.ac.uk](neil. rajan@newcastle.ac.uk)  \n[K. H. and J.I. are joint first authors.](K. H. and J.I. are joint first authors.)  \nAbstract  \nBackground CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. Patients with CCS lack medical therapies and require repeated surgery to control tumour burden. CYLD loss of heterozygosity drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical nuclear factor kappa B (NF-κB) and Wnt signalling.  \nObjectives To investigate NF-κB signalling in CCS tumours and CCS tumour keratinocytes, with the aim of identifying druggable targets.  \nMethods We used complementary bulk transcriptomics and proteomics in patient-derived CCS tumour cell fractions, as well as single-cell RNA sequencing of CCS tumour cells to investigate aberrant NF-κB signalling. We developed a patient-derived CCS tumour spheroid culture model to determine the utility of targeting aberrant NF-κB cell signalling.  \nResults We demonstrate evidence of non-canonical NF-κB signalling in CCS tumour keratinocytes, with increased p100 to p52 processing and RelB protein expression compared with normal skin. We identify IκB kinase alpha (IKKα) as a candidate target in the noncanonical NF-κB signalling pathway. A novel, highly selective IKKα inhibitor (SU1644) used in patient-derived CCS tumour spheroid cultures demonstrated that IKKα inhibition reduced tumour spheroid viability.  \nConclusions These data provide the preclinical rationale for the assessment of topical IKKα inhibitors as a novel preventive treatment for CCS.  \nLay summary  \nCYLD cutaneous syndrome is a rare genetic condition that can lead to the development of skin tumours. These appear mainly on a person’s scalp, face and torso. The condition is known as ‘CCS’ for short. It is caused by changes in a gene called ‘CYLD ’. This gene usually controls a pathway in the body that is involved in inflammation and cell growth. This pathway is known as the ‘NF-κBpathway’. When the CYLD gene is faulty, the NF-κB pathway becomes overactive, leading to skin tumour formation. The tumours can grow from puberty and may become cancerous. Apart from surgery, no medical treatments are available for the condition. People often need to have many surgeries to remove","cbCaikLK5qe4qD7n","https://ap.wps.com/l/cbCaikLK5qe4qD7n","pdf",3882607,12,"English","# Abstract\n## Background\n## Objectives\n## Methods\n## Results\n## Conclusions\n## Lay summary\n# Graphical Abstract\n## What is already known about this topic?\n## What does this study add?","[{\"question\":\"What problem does this study address in CYLD cutaneous syndrome (CCS)?\",\"answer\":\"CCS patients develop many progressively growing skin tumours after puberty and currently have no medical therapies, requiring repeated surgeries to manage tumour burden.\"},{\"question\":\"Which signalling pathway alteration is the study focused on?\",\"answer\":\"The study investigates noncanonical nuclear factor kappa B (NF-κB) signalling in CCS tumour cells and tumour keratinocytes, beyond previously reported canonical NF-κB activity.\"},{\"question\":\"What is the key drug target identified, and what effect was observed?\",\"answer\":\"IκB kinase alpha (IKKα) was identified as a candidate target. A selective IKKα inhibitor (SU1644) reduced tumour spheroid viability in patient-derived CCS tumour models.\"}]","Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha | PDF",1790109372]