Synergistic Antitumor Activity of SUMO1 degrader and Oxaliplatin through G6PD Inhibition in Colorectal Cancer

Colorectal cancer (CRC) stands as one of the primary causes of death despite advancements in targeted therapies and chemotherapeutic methods. The oxaliplatin-based chemotherapy, such as the FOLFOX, remains limited by its toxic side effects and the development of drug resistance. The current studies demonstrate redox homeostasis as an important therapeutic target in cancer cells through the discovery of glucose-6-phosphate dehydrogenase (G6PD) as their major controller of oxidative stress and survival. In this study, we investigated the therapeutic potential of HB007 in combination with FOLFOX in CRC. Treatment with HB007 decreased the enzyme activity of G6PD and generated high ROS concentrations, which subsequently induced intrinsic apoptosis. When combined with FOLFOX, which also induces ROS and inhibits G6PD activity, HB007 showed synergistic cytotoxicity in vitro, in colon patient-derived 3D organoids, and in vivo patient-derived xenograft model, including FOLFOX-resistant tumors. The combination treatment mechanistically targeted G6PD activity, disrupted redox balance, and activated apoptosis without affecting G6PD protein level. These findings suggest that G6PD inhibition by HB007 enhances the efficacy of FOLFOX, suggesting a strategy to overcome chemoresistance and improve therapy in advanced CRC.