Mutant Isocitrate Dehydrogenase Driven Metabolic Reprogramming Results In Therapeutic Vulnerability To Lactate Dehydrogenase Inhibition

Abstract Mutant isocitrate dehydrogenase (mIDH), with a gain-of-function in the production of an oncometabolite (R)-2-hydroxyglutarate (2-HG), is considered as a promising target for cancers carrying IDH mutations. IDH1 mutations, typically involving an amino acid substitution in the active site of the enzyme in codon 132, have been identified in a broad spectrum of solid tumors. The massive production of 2-HG remodels the metabolic network in cancer cells and results in epigenetic alterations facilitating malignant phenotypes. Of note, while the pharmacological inhibition of mIDH1 effectively leads to the remarkable reduction in the intracellular 2-HG level, it seems not associated with the sufficient suppression of solid tumor growth. We hence asked whether it is possible to identify extra metabolic vulnerability in IDH1 mutant tumors. To this end, we performed 13C isotope tracing analysis of glucose and glutamine, two major nutrient supply for 2-HG production, in solid tumor cell lines including HT1080 cells with spontaneous IDH1 mutation and IDH1 mutant glioma cell lines expressing mIDH1. [U-13C6]-glucose tracking enabled us to discover that IDH1 mutated tumors exhibit increased glycolysis and decreased tricarboxylic acid (TCA) metabolism, which can be reversed by mIDH1 inhibition. Meanwhile, cell mitochondrial stress test indicated decreased oxygen consumption rate (OCR) compared with the wildtype counterpart. These data suggest that 2-HG production paralyzes TCA metabolism and subsequent oxidative phosphorylation but enhances aerobic glycolysis, thus reprogramming tumor cells prone to Warburg effect. In line with this hypothesis, lactate dehydrogenase (LDH) inhibition that shut down lactate production increased 2-HG levels in IDH1 mutant cells. Further, LDH inhibition obtained the improved response in IDH1 mutant tumors while combined inhibition of mIDH1 abolished this effect. Together, we discovered that mutant IDH1 impaired TCA cycle by production of millimolar level 2HG which may lead to more dependency on glycolysis. Citation Format: Aiwei Bi, Jun Xu, Nan Jin, Xiaojing Lan, Shuai Tang, Matthew Shou, Jia Liu, Jian Ding, Meiyu Geng, Shuhai Lin, Min Huang. Mutant isocitrate dehydrogenase driven metabolic reprogramming results in therapeutic vulnerability to lactate dehydrogenase inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3737.