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

Abstract

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