Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha

Abstract

CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. CCS patients lack medical therapies and require repeated surgery to control tumour burden. CYLD loss of heterozygosity (LOH) drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical NF-κB and Wnt signalling. Here, we demonstrate evidence of non-canonical NF-κB signalling in CCS tumour keratinocytes, with increased p100 to p52 processing and RelB protein expression compared to normal skin. Utilizing complementary transcriptomics and proteomics on patient derived CCS tumour cell fractions, we identify IκB kinase alpha (IKKα) as a candidate target in the non-canonical 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. These data provide the pre-clinical rationale for the assessment of topical IKKα inhibitors as a novel preventative treatment for CCS.