Targeting noncanonical nuclear factor kappa B signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha.
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ICR Authors
Authors
Hodgson, K
Inns, J
Reynolds, G
Stephenson, E
Paul, A
Sinclair, N
Berretta, G
Lawson, C
Frey, AM
Ivanova, I
Adam, E
Lord, CJ
Cockell, S
Coxhead, J
Nagy, N
Adams, D
Szell, M
Trost, M
Haniffa, M
Mackay, SP
Perkins, N
Rajan, N
Inns, J
Reynolds, G
Stephenson, E
Paul, A
Sinclair, N
Berretta, G
Lawson, C
Frey, AM
Ivanova, I
Adam, E
Lord, CJ
Cockell, S
Coxhead, J
Nagy, N
Adams, D
Szell, M
Trost, M
Haniffa, M
Mackay, SP
Perkins, N
Rajan, N
Document Type
Journal Article
Date
2026-05-19
Date Accepted
2026-02-04
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.
Citation
British Journal of Dermatology, 2026, pp. ljag044 -
Source Title
British Journal of Dermatology
Publisher
OXFORD UNIV PRESS
ISSN
0007-0963
eISSN
1365-2133
Collections
Research Team
Precision Oncology Lord