Targeting cellular metabolism to enhance radiotherapy response in <i>KRAS^mutant</i> non-small cell lung cancer

Gain-of-function <i>KRAS</i> mutations in NSCLC are associated with a more aggressive phenotype and poorer prognosis in a disease which already has low survival rates. Radiotherapy (RT) is a common treatment modality in these cancers and, with <i>KRAS</i> mutations known to confer radioresistance, there is an unmet need to develop novel strategies to improve the efficacy of RT in the <i>KRAS^mutant</i> NSCLC setting.<br><br>Previous studies have shown that modulation of hexose sugar metabolism using mannose can inhibit cell growth and enhance chemotherapy response in multiple cancer types.

In this study, we aimed to evaluate the radiation response modifying properties of mannose in <i>KRAS^mutant</i> NSCLC cell and mouse models of the disease. Radiation response to mannose sugar was investigated in cell models by radiobiological assays and the efficacy of mannose as a radiosensitizing agent was investigated in relevant pre-clinical <i>in vivo</i> models. Liquid chromatography-mass spectrometry (LC-MS) based metabolomics and cytokine arrays were also employed to determine the metabolic perturbations and immune modulating effects of this novel combination treatment in <i>KRAS^mutant</i> NSCLC cells.<br><br>We discovered that mannose sensitised multiple cell models to radiation treatment by preventing the repair of DNA double strand breaks (DSBs) and causing cell cycle arrest at the G1/S checkpoint.