Abstract 4456: De novo pyrimidine synthesis is a druggable vulnerability for chemotherapy resistant nasopharyngeal carcinoma with wild type IDH1

Abstract

Abstract Chemotherapy resistance is a major obstacle to treat nasopharyngeal carcinoma (NPC), and strategies to overcome this resistance are required. Using proteomic analysis, we found that NPC patients resistant to gemcitabine plus cisplatin (GP) induction chemotherapy were characterized by abundant metabolic pathways. NPC with high expression of wild-type isocitrate dehydrogenase 1 (wtIDH1) was hyperdependent on de novo pyrimidine nucleotide synthesis and resistant to GP. Knockdown of IDH1 augmented the inhibition of de novo pyrimidine nucleotide synthesis induced by gemcitabine and cisplatin but reversed the suppression of purine nucleotide synthesis, which leading to DNA damage caused by nucleotide pool imbalance. IDH1 facilitated transcription of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme for de novo pyrimidine nucleotide synthesis, through promoting chromatin accessibility by ALKBH5 in an α-ketoglutaric acid dependent manner. DHODH inhibitor, BAY2402234 significantly sensitized NPC cells to gemcitabine plus cisplatin chemotherapy. Collectively, these results reveal that wtIDH1-induced increase in de novo pyrimidine nucleotide represents a metabolic vulnerability that can be exploited pharmacologically, highlighting BAY2402234 as a promising strategy to enhance the efficacy of chemotherapy against NPC. Citation Format: Yingqin Li, Yuheng Zhao, Wuqi Zhang, Chunxian Ou, Jiaxi Shen, Jun Ma. De novo pyrimidine synthesis is a druggable vulnerability for chemotherapy resistant nasopharyngeal carcinoma with wild type IDH1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4456.