CYLD: A Key Factor and Novel Predictive Biomarker of Cross-Resistance to Chemotherapy and Radiotherapy in Oral Squamous Cell Carcinoma.

Cross-resistance to chemotherapy and radiotherapy is a major obstacle in cancer treatment and strongly associated with poor prognosis. Particularly, oral squamous cell carcinoma (OSCC) frequently exhibits such cross-resistance, limiting the efficacy of standard chemoradiotherapy. To unveil its molecular mechanism, we took advantage of a comprehensive proteomic analysis using clinically relevant radio-resistant OSCC cells, and identified distinct alterations in protein expression. Among the differentially expressed proteins, we focused on the down-regulation of cylindromatosis (CYLD), a deubiquitinating enzyme and tumor suppressor. Suppression of CYLD expression in OSCC cells led to accumulation of DNA damage and increased cross-resistance. CYLD down-regulation caused cross-resistance in OSCC cells, at least in part, via NF-κB hyperactivation. Notably, EGFR-TKI monotherapy demonstrated significant efficacy against cross-resistant OSCC in vitro and in vivo. Moreover, in patient-derived xenograft (PDX) models, CYLD expression might serve as a potential predictive biomarker for EGFR-TKI responsiveness in cross-resistant OSCC. These findings highlight the pivotal role of CYLD down-regulation driving OSCC progression via cross-resistance and offer new prospects for the clinical application of EGFR-TKIs, with CYLD expression serving as a potential predictive biomarker for OSCC patient with cross-resistance.