Transcriptional Expression of SLC2A3 and SDHA Predicts the Risk of Local Tumor Recurrence in Patients with Head and Neck Squamous Cell Carcinomas Treated Primarily with Radiotherapy or Chemoradiotherapy

Reprogramming of metabolic pathways is crucial to guarantee the bioenergetic and biosynthetic demands of rapidly proliferating cancer cells and might be related to treatment resistance. We have previously demonstrated the deregulation of the succinate pathway in head and neck squamous cell carcinoma (HNSCC) and its potential as a diagnostic and prognostic marker. Now we aim to identify biomarkers of resistance to radiotherapy (RT) by analyzing the expression of genes related to the succinate pathway and nutrient flux across the cell membrane. We determined the transcriptional expression of succinate receptor 1 (SUCNR1), succinate dehydrogenase A (SDHA), and the solute carrier (SLC) superfamily transporters responsible for the influx or efflux of a wide variety of nutrients (SLC2A3 and SLC16A3) in tumoral tissue from 120 HNSCC patients treated with RT or chemoradiotherapy (CRT). Our results indicated that the transcriptional expression of the glucose transporter SLC2A3 together with SDHA had the best predictive capacity for local response after treatment with RT or CRT. High SLC2A3 and SDHA expression predicted poor outcomes after RT or CRT, with these patients having a 4.2 times higher risk of local recurrence compared to the rest of the patients. These results might indicate that tumors that shifted toward a higher glucose influx and a higher oxidation of succinate via mitochondrial complex II present an ideal environment for radioresistance development. Patients with a high transcriptional expression of both SLC2A3 and SDHA had a significantly higher risk of local recurrence after treatment with RT or CRT.