Enhancing Rectal Cancer Radiosensitivity and Gut Protection through Methionine Restriction

Purpose Approximately one-third of colorectal cancer cases involve the rectum, where radiation therapy is an integral part of the treatment of this disease. However, KRAS mutations are associated with poor clinical outcomes and lower therapeutic responses. Previous studies suggest that KRAS mutations may alter the balance of metabolites in the methionine cycle. This study investigates the interplay between the methionine cycle, KRAS mutations, and radiation therapy. Experimental Design We examined the impact of the KRAS mutation and radiation on methionine cycle metabolites. In vitro , we reduced methionine levels in the culture media and assessed the radiosensitivity of KRAS-mutant colorectal cancer cells. In vivo , we used an orthotopic mouse model with KRAS-mutant rectal tumors to evaluate the effects of a methionine-restricted (MR) diet on tumor response to radiation. Additionally, we assessed the impact of MR on normal human intestinal epithelial cells and tissues. Results In vitro , MR increased the radiosensitivity of KRAS-mutant cells, with reduced proliferation and increased DNA damage markers following radiation. In vivo , KRAS mutant tumors in mice fed an MR diet showed an increased response rate to radiation compared to KRASwt tumors. Normal cells and tissues showed reduced DNA damage markers under MR conditions, with MR diet improving villus height and crypt depth following abdominal irradiation in mice. Conclusion KRAS-mutant rectal cancer cells rely on methionine for growth, and MR enhances tumor radiosensitivity while protecting normal tissues from radiation-induced damage. These findings suggest that MR may serve as a potential therapeutic strategy to improve treatment outcomes for rectal cancer, particularly in KRAS-mutant tumors.