Metastasis is responsible for the majority of breast cancer-related mortality. Through systematic testing of breast cancer cell lines in vivo, we have identified a strong correlation between metastatic potential and genetic dependency on Dihydroorotate dehydrogenase (DHODH), an inter-mitochondrial gene required for de novo pyrimidine biosynthesis. We determined the consequences of pharmacologic inhibition of DHODH in breast cancer. With Brequinar, a small molecule inhibitor of DHODH. During short-term drug treatments, Brequinar decreased cell viability at high concentrations in metastatic cell lines but was insufficient to completely eliminate cells. During long-term drug treatments, we have found Brequinar to be more effective at killing cells at lower concentrations. In addition, we utilized CRISPRi and CRISPR knockout technology to target and regulate the expression of DHODH. By identifying the potential effects of DHODH inhibition, we are working towards a more holistic understanding of the genes that breast cancer is most reliant on and determining potential directions for treatments.
