Dihydroorotate dehydrogenase (DHODH) is a pivotal enzyme in the uridine monophosphate (UMP) biosynthetic pathway, primarily found in the inner mitochondrial membrane, catalyzing the conversion of dihydroorotate to orotate. It has emerged as a promising therapeutic target for several malignancies due to the extensive use of de novo pyrimidine synthesis in rapidly proliferating cancer cells.
Our prior research demonstrated that early metabolic reprogramming in cutaneous Squamous Cell Carcinoma (cSCC) progression is driven by DHODH activation. In this study, we aimed to evaluate the functional impact of these metabolic variations on cSCC tumor characteristics and their response to DHODH inhibition.
We analyzed the metabolic profiles of 8 cSCC cell lines using extracellular flux analyses to measure the extracellular acidification rate and oxygen consumption rate. Based on glycolysis rates, oxidative phosphorylation, and mitochondrial complex activities, we identified two distinct metabolic profiles among the cell lines. Transplantation of these cell lines into NSG mice revealed different aggressiveness and metastatic potential.
Importantly, the effectiveness of DHODH inhibition (using leflunomide, LFN) in suppressing tumor growth and metastatic potential was dependent on the metabolic profiles of the cell lines. DHODH expression levels varied across the cell lines and served as a predictive marker for sensitivity to DHODH inhibition. Overexpressing DHODH in LFN-resistant cell lines made them susceptible to DHODH inhibition.
Targeting DHODH may be an effective therapeutic strategy for a subset of cSCC with specific metabolic profiles, and DHODH expression levels could serve as a predictive biomarker for the response to DHODH inhibition-based metabolic therapy.