Cysteine addiction in drug resistant glioblastoma and therapeutic targeting with designer selenium compounds

AbstractAbstract: Background: 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, including the standard care for glioblastoma (GBM), temozolomide (TMZ), we hypothesized that TMZ-resistant (TMZ-R) GBM would have increased ROS affecting cysteine reactivity that could be therapeutically targeted. Methods: Here, to study the metabolic state within drug sensitive and resistant GBM, we used metabolite tracing with¹³ C-Cyst(e)ine, specialized cysteine reactivity proteomics and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening with drug treatments to determine the efficacy of targeting cysteine metabolic pathways with our designer selenium drug in both patient-derived cell lines and patient-derived xenograft GBM ­orthotopic models. Results: We show that TMZ-R have increased cyst(e)ine uptake, cysteine reactivity, and sensitivity to selenium (Se)-containing compounds—which can bind cysteine—in vitro and in vivo. 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 significantly improves overall survival in mouse models. Conclusions: Overall, our findings show a unique metabolic environment in TMZ-R models where designer brain penetrant Se-containing compounds target cysteine reactivity within proteins necessary for cancer cell survival and hold therapeutic potential.