High-Fat Diet Fuels Mutation in Melanoma Cells

The BRAF V600E mutation in melanoma thrives on a high-fat diet, which increases its growth rate, according to a study published in Cell Metabolism.

The mutation is found in more than 60% of melanomas and all of the hairy cell type of leukemia, as well as a subset of colorectal cancers (10%) and multiple myelomas (5%). Although there are drugs on the market that target the BRAF V600E mutation, treatment resistance is common.

Through prior research, the investigators found that the V600E mutation rewires cancer cell’s metabolism, resulting in the stimulation of the ketogenesis pathway. The ketogenesis pathway breaks down fats for energy when glucose levels are low.

An alternative energy source that ketogenesis produces is acetoacetate. In cancer cells with the mutation, acetoacetate production is stimulated. Furthermore, acetoacetate binds the mutated B-raf protein and promotes its oncogenic activity, forming a cycle of positive feedback.

In the new study, the investigators sought to test whether V600E cancer cells responded to external acetoacetate. According to the authors, a ketogenic diet with very low carbohydrates can cause acetate levels to rise. Additionally, fasting can have the same effect.

Mice were fed a diet containing more than 90% of its calories from fat. The results of the study showed grafted tumors derived from V600E melanoma cells grew twice as large over 4 weeks compared with mice fed a normal diet. These findings were not true of tumors from melanoma cells with other oncogenic mutations.

Lipid-lowering drugs­—–such as statins, niacin, and fenofibrate––that are commonly used to treat high cholesterol, could slow cancer growth in mice with V600E tumors even those fed a normal diet.

“Lipid-lowering agents may have a role in cancer prevention or supplemental treatment approaches to reduce cancer progression or improve clinical outcomes in the BRAF V600E-positive pre-malignancy and cancer settings,” said senior author Jing Chen, PhD. “Limiting dietary fat intake and monitoring circulating acetoacetate levels might be beneficial in patients with BRAF V600E melanoma or other related cancers. At this point, we can’t be specific about diet suggestions, because we need to know more about what types of dietary fat trigger acetoacetate production.”

The chemical dehydroacetic acid, which structurally resembles acetoacetate, inhibits the effect of acetoacetate on V600E tumor growth. Currently, dehydroacetic acid is used in cosmetics and appears to have low toxicity, according to the study. However, more research needs to be done to determine its anti-cancer properties, especially at levels that could alter cell metabolism.