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

Hodgson, K.; Inns, J.; Reynolds, G.; Stephenson, E.; Paul, A.; Sinclair, N.; Berretta, G.; Lawson, C.; Frey, A. M.; Ivanova, I.; Adam, E.; Lord, C. J.; Cockell, S.; Coxhead, J.; Nagy, N.; Adams, D.; Szell, M.; Trost, M.; Haniffa, M.; Mackay, S.; Perkins, N.; Rajan, N.

doi:10.1101/2025.01.31.635629

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bioRxiv · 10.1101/2025.01.31.635629

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

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Abstract

CYLD cutaneous syndrome (CCS) skin tumors 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 tumor burden. CYLD loss of heterozygosity (LOH) drives tumor growth, and CCS tumors have previously been shown to demonstrate increased canonical NF-{kappa}B and Wnt signalling. Here, we demonstrate evidence of non-canonical NF-{kappa}B signalling in CCS tumor keratinocytes, with increased p100 to p52 processing and RelB protein expression compared to normal skin. Utilizing complementary transcriptomics and proteomics on patient derived CCS tumor cell fractions, we identify I{kappa}B kinase alpha (IKK) as a candidate target in the non-canonical NF-{kappa}B signalling pathway. A novel, highly selective, IKK inhibitor (SU1644) used in patient derived CCS tumor spheroid cultures demonstrated that IKK inhibition reduced tumor spheroid viability. These data provide the pre-clinical rationale for the assessment of topical IKK inhibitors as a novel preventative treatment for CCS. TeaserTopical IKK inhibition emerges as a potential therapy for CYLD cutaneous syndrome by targeting non-canonical NF-{kappa}B signalling Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/635629v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@829218org.highwire.dtl.DTLVardef@459f5dorg.highwire.dtl.DTLVardef@e198f6org.highwire.dtl.DTLVardef@1015685_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Hodgson, K., Inns, J., Reynolds, G., Stephenson, E., Paul, A., Sinclair, N., Berretta, G., Lawson, C., Frey, A. M., Ivanova, I., Adam, E., Lord, C. J., Cockell, S., Coxhead, J., Nagy, N., Adams, D., Szell, M., Trost, M., Haniffa, M., Mackay, S., Perkins, N., Rajan, N.. 2025-02-03. Targeting non-canonical NF-κB signalling in CYLD cutaneous syndrome by selective inhibition of IκB kinase alpha.. https://doi.org/10.1101/2025.01.31.635629

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