Abstract

Reactive oxygen species (ROS) are a double-edge sword in cancers and can both promote pro-tumorigenic signaling and also trigger oxidative stress dependent cell death. Thus, maintaining redox homeostasis to control levels of ROS within a tumor-promoting range elicits critical tumorigenic potential in cancer. Here, we show that head and neck squamous cell carcinoma (HNSCC) is uniquely characterized by its critical dependence on heightened antioxidant capacity facilitated by elevated glucose uptake to maintain survival and proliferation. Using a basal-epithelial-layer-specific GLUT1 knockout mouse model, we establish that targeting GLUT1-mediated glucose utilization in HNSCC cells of origin robustly inhibits HNSCC progression, providing strong genetic evidence that GLUT1 is indeed a targetable metabolic vulnerability. We further demonstrate that disrupting redox homeostasis with prooxidants such as high dose vitamin C and Auranofin induces potent cytotoxicity in HNSCCs by exerting profound oxidative stress when combined with GLUT1 inhibitors. Given the central role of insulin signaling in glucose homeostasis, we additionally show that circulating insulin levels modulate metabolic and oncogenic pathways of HNSCCs, providing a new perspective on events driving and sustaining HNSCC malignancy. These results establish GLUT1 as a viable therapeutic target for HNSCC in combination with prooxidant chemotherapies and define critical dependencies in HNSCC that can be utilized with existing clinical stage drugs for the treatment of HNSCC and potentially other squamous cancers.