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

ABSTRACT: 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 al

SUBMITTER: Cardenas H 

PROVIDER: S-EPMC12578261 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature