Dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in the uridine monophosphate (UMP) biosynthetic pathway and it is mostly located in the inner membrane of mitochondria, catalyzing the transformation of dihydroorotate to orotate. DHODH has emerged as a new therapeutic target in a wide spectrum of malignancies as de novo pyrimidine synthesis is extensively used in rapidly proliferative cancer cell lines. Here, we aimed to identify the functional impact of the potential detected metabolic heterogeneities on tumor features of cSCC and their responses to DHODH inhibition. Concerning metabolic heterogeneities, we first characterized the metabolic features of 8 cSCC cell lines through measurement of extracellular acidification rate and oxygen consumption rate using extracellular flux analyses. Based on the rates of glycolysis, oxidative phosphorylation and mitochondrial complexes activities, we stratified these cell lines in two metabolic profiles. Evaluation of tumor growths after transplantation of these cell lines into NSG mice revealed that cell lines with different metabolic profiles exhibited different features, namely different aggressiveness and metastasis. Interestingly, the inhibitory efficiency of DHODH on tumor growth and metastatic potency also depended on metabolic profiles of the cells. We found that the expression level of DHODH was also different among cell lines and can be a marker to predict the sensitivity to DHODH inhibition. DHODH overexpression in refractory cell lines rendered them sensitive to DHODH inhibition. Thus, our data suggest that targeting DHODH through disruption of the pyrimidine biosynthesis is a potential therapeutic target in a subgroup of cSCC with a particular metabolic profile and that DHODH expression level can be used as a predicted biomarker of response to DHODH inhibition-based metabolic therapy.

ESDR480 - Inhibition of DHODH reduces efficiently tumor growth in a subgroup of cutaneous squamous cell carcinoma with a particular metabolic profile

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