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

Abstract

Mutant KRAS is a key driver oncogene in non-small cell lung cancer (NSCLC) with functional roles in various pathways including cellular proliferation, survival and metabolism. Gain-of-function KRAS 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 KRAS mutations known to confer radioresistance, there is an unmet need to develop novel strategies to improve the efficacy of RT in the KRAS^mutant NSCLC setting.

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 KRAS^mutant 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 in vivo 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 KRAS^mutant NSCLC cells.

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. Our LC-MS metabolomics analysis indicated that treatment with mannose and radiation in combination has a pronounced effect on tumour cell metabolism particularly the glutathione biosynthesis pathway, with significant increases in antioxidant production observed. Mannose and radiation combination was also shown to modulate cytokine secretion, with decreases in the levels of multiple pro-tumour cytokines detected. These data highlight mannose supplementation as a promising radiosensitizing strategy that could be beneficial for improving RT outcomes in KRAS^mutant NSCLC.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Karl Butterworth (Supervisor) & Emma Kerr (Supervisor)