Metabolic Dependency on De Novo Pyrimidine Synthesis Is a Targetable Vulnerability in Platinum-Resistant Ovarian...

Ovarian cancer is lethal because of near-universal development of resistance to platinum-based chemotherapy. Metabolic adaptations can play a pivotal role in therapy resistance. In this study, we aimed to identify key metabolic pathways that regulate platinum response and represent potential therapeutic targets. Transcriptomic and metabolomic analyses in cisplatin-sensitive and -resistant ovarian cancer cells identified enrichment of pyrimidine metabolism related to upregulated de novo pyrimidine synthesis. The 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in cisplatin-resistant cells. Targeting this pathway using brequinar (BRQ), an inhibitor of the key enzyme dihydroorotate dehydrogenase, decreased cell viability, delayed G2/M cell-cycle progression, and altered expression of genes related to mitochondrial electron transport in resistant cells. Under basal conditions, cisplatin-resistant cells had a lower oxygen consumption rate and spare respiratory capacity than cisplatin-sensitive cells. BRQ suppressed the oxygen consumption rate in both sensitive and resistant cells but only inhibited spare respiratory capacity in resistant cells. In cell line-derived and patient-derived xenograft models, BRQ attenuated the growth of cisplatin-resistant ovarian tumors and enhanced the inhibitory effects of carboplatin. Together, these results identify metabolic reprogramming in cisplatin-resistant ovarian cancer that induces an acquired dependency on de novo pyrimidine synthesis, which can be targeted to sensitize tumors to chemotherapy.

De novo pyrimidine synthesis supports platinum resistance in ovarian cancer and can be targeted with DHODH inhibitors to suppress tumor growth, pointing to potential metabolic therapies for treating recurrent ovarian cancer.