Gene Mutation Could Be Target for “Ultrapersonalized” Colon Cancer Therapy

Researchers at Fox Chase Cancer Center have identified a distinct metabolic feature linked to a specific mutation in the KRAS gene, which is frequently altered in colon cancer. Their findings, published in Cell Reports, suggest that this variant behaves differently from other common forms of the gene and may be selectively targeted in future therapies.

The KRAS gene has long been associated with cancer development and progression, particularly in colorectal tumors, where it is often mutated. However, emerging evidence suggests that not all KRAS mutations function identically. The study examined three prevalent KRAS variants in colon cancer to explore these functional differences.

Metabolic divergence revealed in mouse models

Using CRISPR gene editing, the research team introduced individual KRAS mutations into mouse colon cells while keeping all other genetic features consistent. This allowed for direct comparisons of how each mutation influenced cellular behavior.

One mutation, known as KRAS G12V, exhibited a unique metabolic profile. All three variants played a role in synthesizing acetyl-CoA, a molecule essential for producing fatty acids and proteins. However, KRAS G12V utilized a different enzyme for this process, diverging from the pathway seen in the other two mutations.

Acetyl-CoA is a key metabolite in cellular metabolism, often described as a precursor for numerous biosynthetic reactions. The altered synthesis pathway in KRAS G12V cells suggested a potential vulnerability that might be exploited therapeutically.

Potential for targeted inhibition

Further analysis showed that inhibiting the enzyme uniquely used by KRAS G12V disrupted acetyl-CoA production in those cells. This sensitivity was confirmed in additional cell line studies and mouse models, indicating that KRAS G12V–driven tumors might respond to drugs blocking this specific metabolic route.

These results provide early-stage evidence that individual KRAS mutations may require distinct therapeutic approaches. While past research has often treated all KRAS mutations similarly, this study supports the idea that precision targeting of specific variants may improve treatment outcomes.

Implications for broader cancer research

The team plans to expand their investigations to other cancer types, including pancreatic and lung cancers, where KRAS mutations are also common. Before any clinical applications, further testing in human cell and organoid models of colon cancer will be necessary.

This research emphasizes the importance of understanding functional differences among gene variants within the same oncogene and how such differences might shape new therapeutic directions.

Reference: Budagyan K, Cannon AC, Chatoff A, et al. KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation. Cell Rep. 2025;44(4):115444. doi: 10.1016/j.celrep.2025.115444

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