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

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 drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical NF-KB and Wnt signalling. Here, we demonstrate evidence of non-canonical NF-κB signalling in CCS tumours, with increased p100 to p52 processing and RelB protein expression. Utilising 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 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 treatment for CCS. Here we provide CellRanger processed data and an annotated anndata object (.h5ad).CYLD皮肤综合征（CYLD cutaneous syndrome, CCS）患者的皮肤肿瘤自青春期起发作，数量可达数百个，且随时间推移进行性增大。目前CCS患者尚无获批治疗药物，需反复接受手术以控制肿瘤负荷。CYLD杂合性缺失可驱动肿瘤生长，既往研究已证实CCS肿瘤存在经典NF-κB及Wnt信号通路的异常激活。本研究首次在CCS肿瘤中发现非经典NF-κB信号通路活化的证据，表现为p100向p52的加工过程增强以及RelB蛋白表达上调。通过对患者来源的CCS肿瘤细胞组分开展互补的转录组学与蛋白质组学分析，我们鉴定出核因子κB抑制蛋白激酶α（IκB kinase alpha, IKKα）作为非经典NF-κB信号通路中的潜在治疗靶点。在患者来源的CCS肿瘤球体培养模型中，一种新型高选择性IKKα抑制剂可显著降低肿瘤球体的存活率。上述数据为评估外用IKKα抑制剂作为CCS新型治疗方案提供了临床前依据。本数据集包含经CellRanger处理的测序数据及注释后的anndata对象（.h5ad格式）。