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

作者：Horacio Cárdenas, Yinu Wang, Guangyuan Zhao, Dengrong Hao, Ana Maria Isac, Vanessa Hernandez, U.K. Kim, Wenan Qiang, Hao F. Zhang, Daniela Matei · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-25-0043 · 被引用次数：7 · 研究领域：Biochemical and Molecular Research、Biochemical Acid Research Studies、Cancer, Hypoxia, and Metabolism

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 no...