The KRAS gene is a frequent site of mutation in colorectal cancer, affecting approximately 40% of all cases. This gene provides instructions for making a protein that acts like a switch governing cell behavior. The presence of a KRAS mutation significantly influences the course of the disease and dictates which treatments a patient can or cannot receive. Identifying the specific KRAS status of a tumor is a necessary step in managing colorectal cancer.
How the KRAS Gene Causes Cancer
The KRAS gene encodes the K-Ras protein, a small enzyme that functions as a molecular switch in the cell’s signaling network, particularly the RAS/MAPK pathway. In its normal, or “wild-type,” state, the K-Ras protein cycles between an inactive state (bound to GDP) and an active state (bound to GTP) to relay signals from the cell surface to the nucleus. These signals regulate cell growth, division, and maturation.
When a mutation occurs, it often impairs the protein’s ability to convert GTP back to GDP, which turns the switch off. The K-Ras protein becomes permanently “stuck in the on position,” similar to an accelerator pedal jammed down. This constant activation bombards the cell nucleus with growth signals, leading to uncontrolled cell proliferation and tumor formation. The most common activating mutations are found in codons 12 and 13, such as G12D, G12V, and G12C, which drive colorectal cancer development.
Detecting the Mutation in Colon Cancer
Testing for the KRAS mutation is a standard procedure following a colorectal cancer diagnosis. This testing is performed on tumor tissue, typically collected through a biopsy or surgical resection, to accurately determine the genetic profile of the cancer before selecting a treatment plan.
Specialized laboratory techniques, such as molecular sequencing or polymerase chain reaction (PCR), analyze the tumor DNA for specific alterations in the KRAS gene. Identifying the exact variant, like G12D or G12C, is essential because treatment strategies depend on the precise mutation present. Because the result of this test directly influences treatment options, it is considered a predictive biomarker.
Treatment Implications for Standard Therapies
The presence of a KRAS mutation acts as a negative predictive biomarker, forecasting a lack of benefit from certain established targeted therapies. Patients with KRAS-mutated colorectal cancer are not candidates for anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. These drugs function by binding to the Epidermal Growth Factor Receptor (EGFR) on the cell surface, which normally sends signals down to the K-Ras protein.
Anti-EGFR agents block the initial signal being sent to the cell. However, when K-Ras is mutated, it is already locked in its active, “on” state, bypassing the need for the upstream EGFR signal. Blocking EGFR at the surface therefore has no effect on the constantly active, mutated K-Ras protein, rendering the treatment ineffective.
For patients with this mutation, the standard first-line approach involves traditional chemotherapy regimens, often combined with other biological agents that target different pathways, like bevacizumab. This strategy relies on non-targeted, cytotoxic effects to kill rapidly dividing cells.
New Drugs Targeting Specific KRAS Variants
The challenge of targeting the K-Ras protein, long considered “undruggable,” has been overcome by developing small molecule inhibitors for specific variants. The first major breakthrough focused on the KRAS G12C mutation, which accounts for less than 10% of KRAS-mutated colorectal cancers. Drugs like sotorasib and adagrasib work by binding to the altered cysteine residue found only in the G12C mutant protein.
This binding locks the G12C protein into an inactive state, turning off the jammed growth signal. However, blocking the G12C variant alone often leads to a quick adaptive response where the cancer cell reactivates the upstream EGFR pathway. To counteract this resistance, these new KRAS inhibitors are often combined with an anti-EGFR antibody, like panitumumab or cetuximab, to block both the mutation and the compensatory signal.
This combined approach has established a new standard of care for patients with the KRAS G12C variant whose disease has progressed after initial chemotherapy. Researchers are actively developing inhibitors for the other, more common KRAS variants, particularly G12D and G12V, which represent the majority of KRAS mutations in colorectal cancer. Early-phase clinical trials are investigating drugs that specifically target the G12D mutation, aiming to expand precision medicine.