EXTH-32. SEQUENTIAL SUNITINIB AND AURANOFIN TREATMENT INDUCEDCYTOTOXICITY THROUGH ROS-MEDIATED MECHANISM IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) displays aberrant expression of several receptor tyrosine kinases (RTKs) leading to worse prognosis. Despite aggressive treatment including surgery, radiation and the alkylating agent temozolomide (TMZ), GBM tumors counteract deleterious effects treatment-induced reactive oxygen species (ROS) resistance standard treatment. Likewise, DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) plays a key role in TMZ.We previously reported potential link between MGMT decreased angiogenesis GBM. The differential affected response sunitinib, multitargeted RTK inhibitor with anti-angiogenic properties FDA-approved different cancer types. Notably, TMZ-resistant MGMT-positive cells were more vulnerable sunitinib compared isogenic MGMT-negative cells. We further provided evidence for positive relationship antioxidant enzyme, thioredoxin reductase 1 (TrxR1) TrxR1-targeting drug Auranofin, rheumatoid arthritis generated ROS induced cytotoxic displaying low TrXR1. hypothesized that sunitinib-induced anti-proliferative might sensitize Auranofin. showed cells, which displayed lower levels TrxR1, Auranofin than scavenger N-acetylcysteine (NAC) reverted cytotoxicity suggesting ROS-mediated effects. Conversely, Sunitinib exhibited ROS-independent Remarkably, sequential using pre-treatment (2 hours) followed by (24 significantly cell viability, clonogenicity, increased ROS, TrXR1 sensitized resistant NAC these synergistic effects, mechanism. Our study provides new insights into modulation cellular redox homeostasis This will enable repurposing two drugs known safety profile an effective therapeutic strategy patients.