IntroductionReprogrammed energy metabolism is one among the distinguished cancer hallmarks that unravels the dysregulated bioenergetics of cancer cells. Isocitrate dehydrogenase 2 (IDH2), a mitochondrial metabolic enzyme has been reported to be overexpressed in several cancers, yet the mechanisms of wildtype IDH2-induced transformation are still obscure. We previously identified IDH2, as a novel poor prognosis marker of breast cancer progression. In agreement, transcriptomics (TCGA) and proteomics data of breast cancer clinical samples showed similar expression changes of increased wildtype IDH2 from luminal, to triple-negative and to HER-2 positive, which correlated with tumour aggressiveness.Material and methodsWe performed intracellular metabolite tracing with heavy labelled glucose (13C6) and glutamine (13C5) followed by ultra-high performance liquid chromatography separation and mass spectrometric analysis on the Q-Exactive Plus instrument. Genome-scale metabolic modelling analysis was performed to identify the IDH2-dependent metabolic genes using Minimization of Metabolic Adjustment (MOMA) algorithm.Results and discussionsOverexpression of IDH2 increased serine biosynthesis, increased glycolytic rate and oxidative stress resistance. Genome-scale metabolic modelling of breast cancer tumour data identified dependence on serine biosynthesis as one of the metabolic vulnerability of IDH2 overexpressing cells. CRISPR-Cas9 mediated knockout of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT) specifically inhibited IDH2 overexpressing cells, even in the presence of exogenous serine and glycine, and reduced the glycolysis rate and glucose uptake. Furthermore, loss of serine synthesis pathway hampered the flux from glycolysis, into the TCA cycle. Moreover the metabolic perturbations of synthetic dosage lethal partners, PHGDH and PSAT sensitised the IDH2 overexpressing cells to oxidative stress.ConclusionThis study reveals WT-IDH2 as a critical metabolic regulator in breast cancer that supports the pro-tumorigenic Warburg effect. These findings may contribute to translate the metabolic dependency to improve targeted therapeutics.