DDDR-08. Cysteine addiction in drug resistant glioblastoma and therapeutic targeting with designer selenium compounds

Abstract Cysteine is a multifunctional amino acid that can be oxidized affecting disulfide bond formation, redox signaling, and protein function. Reactive oxygen species (ROS) and the metabolic environment dictate cysteine uptake and oxidation status – especially in redox sensitive pathways. As many chemotherapeutic agents increase ROS, we show here that temozolomide-resistant glioblastoma models (TMZ-R) have increased cyst(e)ine uptake, oxidized cysteines, and sensitivity to selenium (Se)-containing compounds – which can bind cysteine – in vitro and in vivo. Using chemical proteomics to quantify baseline and Se-interacting cysteines alongside CRISPR screening, we show that in TMZ-R models selenium compound treatment increases the need for thioredoxin reductases where co-treatment of Se compounds and the thioredoxin inhibitor auranofin at sublethal doses specifically synergize in killing TMZ-R cells. Overall, our findings show a unique metabolic environment in TMZ-R models where designer brain penetrant Se-containing compounds target cysteine oxidation within proteins necessary for cancer cell survival and hold therapeutic potential.