UVB is the most significant risk factor of non-melanoma skin cancers, like cSCCs, the most common types of human malignancies worldwide. cSCCs are considered to progress from a precursor AK to in situ, invasive and finally metastasis which is associated with a dismal prognosis and a median survival of less than 2 years. Thus, to preserve the chances to cure cSCCs it is urgent to improve the level of prevention and protection for skin cancer with the evaluation of new therapeutic strategies. Energy metabolism reprogramming plays an important role in the initiation and progression of many types of human tumors but little attention has been given to precise the metabolism rewiring and molecular heterogeneity in skin cancers. Using a multistage model of UVB radiation-induced skin cancer and with a quantitative proteomic and targeted metabolomics approaches, we found that specific metabolic modifications occurs at the very early stage of photocarcinogenesis. We showed that the distal part of electron transport chain (ETC) in mitochondria was upregulated in AK owing to the over-activation of dihydroorotate dehydrogenase (DHODH), an enzyme implied in pyrimidine synthesis. Biochemical functional analysis on human cell lines at different stages of carcinogenesis revealed a positive correlation between stages of tumor development with the following features: oxygen consumption rate (OCR), extra cellular acidification rate (ECAR), glutamine consumption rate and the expression levels of enzymes implicated in pyrimidine biosynthesis. We evaluated the DHODH expression level in human skin at different stages of carcinogenesis. Immunostaining showed a positive correlation between the stages of carcinogenesis and the DHODH expression levels. Finally we tested the effect of leflunomide (LFN), a potent DHODH inhibitor, in our xenograft model. Results showed a significant reduction in tumor growth in mice treated with LFN. Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.

ESDR256 - Metabolic Vulnerabilities as Predictive Biomarkers and Therapeutic Targets in Skin Carcinogenesis

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING