TMET-25. WILD-TYPE IDH1 INHIBITS FERROPTOSIS IN GLIOBLASTOMA

Abstract De novo lipogenesis and the defense against oxidative lipid damage require large amounts of cytosolic NADPH. Our group has recently found that glioblastoma (GBM) up-regulate wild-type Isocitrate dehydrogenase 1 (referred to hereafter as ‘wt-IDH1high GBM) that, through oxidative decarboxylation of isocitrate, generates large quantities of alpha-ketoglutarate and cytosolic NADPH. We demonstrated that RNAi-mediated knockdown of wt-IDH1, alone and in combination with RT, slows the growth of patient-derived HGG xenografts, while overexpression of wt-IDH1 promotes intracranial HGG growth. Here, we demonstrate that wt-IDH1high GBM produce excess NADPH, which is a rate-limiting reductant that drives de novo fatty acid biosynthesis. Isotope tracer and liquid chromatography-based lipidomic studies indicate that wt-IDH1 supports the de novo biosynthesis of mono-unsaturated fatty acids (MUFAs), promotes the incorporation of monounsaturated, and reduces the abundance of oxidizable polyunsaturated (PUFA) phospholipids in the cell membrane. Conversely, the genetic ablation of wt-IDH1 or the pharmacologic inhibition of wt-IDH1 in tumor cells, using a brain-penetrant wt-IDH1-specific small molecule, revealed a significant increase in PUFA-containing lipid species harboring oxidized arachidonic tails. Of note, two lipid species, (PE16:0_20:4) and (PE18:0_22:4), previously reported to act as substrates for 15-lipoxygenase (15-LOX) - a key enzyme that facilitates lipid peroxidation - are enriched in tumor cells with wt-IDH1 compromise. Further, we found that the enhanced NADPH production in wt-IDH1high GBM, together with heightened biosynthesis of carbon precursors required for glutathione biosynthesis, increased levels of reduced glutathione (GSH), activate the phospholipid peroxidase glutathione peroxidase 4 (GPX4)-driven lipid repair pathway, which scavenges PUFA-containing lipid peroxides, known executioners of ferroptosis. These findings support elevated wt-IDH1 expression, the ensuing effect on the tumor lipidome, redox homeostasis, and protection against lipid peroxidation as contributors to GBM tumor growth and therapy resistance and point to the inhibition of wt-IDH1 as a ferroptosis-inducing strategy for the treatment of GBM.