Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha

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Hodgson, Kirsty and Inns, Joseph and Reynolds, Gary and Stephenson, Emily and Paul, Andrew and Sinclair, Naomi and Berretta, Giacomo and Lawson, Christopher and Frey, Andrew Michael and Ivanova, Iglika and Adam, Eva and Lord, Christopher J and Cockell, Simon and Coxhead, Jonathan and Nagy, Nikoletta and Adams, David and Szell, Marta and Trost, Matthias and Haniffa, Muzlifah and Mackay, Simon P and Perkins, Neil and Rajan, Neil (2026) Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha. The British Journal of Dermatology, 194 (6). pp. 1130-1141. ISSN 1365-2133 (https://doi.org/10.1093/bjd/ljag044)

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Abstract

Background 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. Objectives To investigate NF-κB signalling in CCS tumours and CCS tumour keratinocytes, with the aim of identifying druggable targets. Methods 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. Results 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. Conclusions These data provide the preclinical rationale for the assessment of topical IKKα inhibitors as a novel preventive treatment for CCS.

ORCID iDs

Hodgson, Kirsty, Inns, Joseph, Reynolds, Gary, Stephenson, Emily, Paul, Andrew ORCID logoORCID: https://orcid.org/0000-0001-5775-2332, Sinclair, Naomi, Berretta, Giacomo ORCID logoORCID: https://orcid.org/0000-0002-8646-9904, Lawson, Christopher ORCID logoORCID: https://orcid.org/0000-0002-0729-182X, Frey, Andrew Michael, Ivanova, Iglika, Adam, Eva, Lord, Christopher J, Cockell, Simon, Coxhead, Jonathan, Nagy, Nikoletta, Adams, David, Szell, Marta, Trost, Matthias, Haniffa, Muzlifah, Mackay, Simon P ORCID logoORCID: https://orcid.org/0000-0001-8000-6557, Perkins, Neil and Rajan, Neil;
CORE (COnnecting REpositories)