Abstract 3073: Metabolic dependency on de novo pyrimidine synthesis in platinum resistant ovarian cancer

Abstract Background: High grade serous ovarian cancer (OC) is lethal due to near universal development of resistance to platinum-based chemotherapy. Materials and Methods: We used cisplatin resistant (Cis-R) cells generated by repeated cisplatin treatment of sensitive (Cis-S) OC cell lines, transcriptomic and metabolomic analyses to identify key metabolic pathways associated with platinum resistance. In vivo experiments used intraperitoneal (ip) OC xenografts and patient derived xenografts (PDX). Results: Pathway analysis of differentially abundant metabolites in Cis-R vs. Cis-S OVCAR5 and COV362 cells identified enrichment of pyrimidine metabolism (FDR<0.05) related to increased de novo pyrimidine synthesis. 15N-glutamine flux analysis confirmed increased de novo pyrimidine synthesis in Cis-R cells. Inhibition of this pathway using the DHODH inhibitor brequinar (BRQ) decreased cell viability and induced expression changes in genes of the mitochondrial electron transport in Cis-R compared with Cis-S cells. Oxygen consumption rate (OCR) measured with a Seahorse assay indicated lower (P<0.05) OCR (baseline, ATP-related, and maximal) and spare respiratory capacity (SRC) in Cis-R vs. Cis-S OVCAR5 cells. BRQ induced dose-related inhibition of OCR in both Cis-R and Cis-S cells. SRC was inhibited by BRQ only in Cis-R cells. In vivo, BRQ attenuated growth of ip Cis-R OC xenografts but did not alter Cis-S tumors. Tumor growth was also inhibited (p<0.01) by BRQ in a Cis-R PDX model. BRQ plus carboplatin enhanced (p<0.05) the inhibitory effects of carboplatin alone in ip Cis-R OC xenografts. Conclusions: Our results support that Cis-R cells acquire dependency on the de novo pyrimidine synthesis and maintain relatively low levels of mitochondrial oxidation, rendering Cis-R cells and tumors vulnerable to inhibitors of this pathway. Citation Format: Horacio Cardenas, Guangyuan Zhao, Ana Maria Isac, Daniela E. Matei. Metabolic dependency on de novo pyrimidine synthesis in platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3073.