Cancer treatment is increasingly adopting a precision medicine approach, tailoring therapies based on the unique genetic characteristics of an individual’s tumor. Molecular testing for specific genetic alterations that drive cancer growth is central to this strategy. The KRAS gene is a key player in cellular signaling, and mutations in this gene are among the most common oncogenic drivers found across various human cancers. Testing for the presence and specific type of KRAS mutation is a routine procedure that directly influences the selection of modern treatment options. This information identifies patients who may benefit from recently developed, highly targeted therapies.
The Role of KRAS Mutations in Cancer Growth
The KRAS gene, located on chromosome 12, instructs the cell to make the K-Ras protein, which functions as a molecular switch. This protein is a guanosine triphosphatase (GTPase) that regulates the RAS/MAPK signaling pathway, governing cell division, growth, and survival. K-Ras normally cycles between an inactive “off” state (bound to guanosine diphosphate, or GDP) and an active “on” state (bound to guanosine triphosphate, or GTP). When active, it relays signals that promote cell proliferation.
In a healthy cell, K-Ras quickly converts GTP back to GDP, turning itself off and halting the growth signal. However, a mutation in the KRAS gene, such as G12C or G12D, alters the protein’s structure, impairing its ability to perform this conversion. The most common mutations occur at codons 12, 13, or 61, with G12 mutations accounting for about 83% of all KRAS alterations. This structural change locks the K-Ras protein into its active, “on” position, regardless of external signals.
The persistent activation of the K-Ras protein drives continuous and uncontrolled cell proliferation, leading to tumor growth. This is why mutated KRAS is classified as an oncogene. The specific location of the mutation (e.g., G12C, G12D, or G12V) determines the downstream signaling preferences and the overall behavior of the cancer.
Cancers Requiring KRAS Testing
Testing for KRAS mutations is standard practice across several cancer types where this gene frequently drives the disease. The most common cancer altered by KRAS is Pancreatic Ductal Adenocarcinoma (PDAC), where over 90% of tumors have a KRAS mutation. In PDAC, the G12D and G12V subtypes are most prevalent, while the G12C mutation is rare, occurring in less than 2% of cases.
KRAS alterations are also a factor in Colorectal Cancer (CRC), found in approximately 45% of cases. In CRC, the presence of any KRAS mutation traditionally excludes certain antibody therapies, such as anti-Epidermal Growth Factor Receptor (EGFR) agents. Non-Small Cell Lung Cancer (NSCLC) also requires KRAS testing, with mutations occurring in about 32% of lung cancers. The KRAS G12C subtype is particularly common in lung adenocarcinomas. The KRAS status in these cancers serves as a predictive biomarker, guiding oncologists to select effective therapy based on the tumor’s specific genetic profile.
The Clinical Process of KRAS Testing
Determining a patient’s KRAS status begins with acquiring a biological sample from the tumor. This sample is typically collected through a tissue biopsy, such as a surgical excision or a needle biopsy. The tissue is then processed and sent to a specialized laboratory for molecular analysis.
Obtaining sufficient and high-quality tumor tissue is not always possible, especially in advanced disease or hard-to-reach locations. In such cases, a non-invasive procedure called a liquid biopsy offers an alternative, involving a simple blood draw. This test analyzes circulating tumor DNA (ctDNA), which are genetic fragments shed by cancer cells into the bloodstream. Liquid biopsy provides a snapshot of the tumor’s genetic makeup and is useful for monitoring disease or when a tissue sample is inadequate.
Once the sample is in the lab, molecular methods detect the exact genetic change. Next-Generation Sequencing (NGS) is the preferred method, as it analyzes millions of DNA fragments simultaneously, providing a comprehensive profile of multiple gene mutations, including all KRAS subtypes. NGS detects variants at a very low frequency and identifies co-occurring mutations, which influence treatment decisions. Other methods, like real-time Polymerase Chain Reaction (PCR), are faster and highly sensitive for detecting specific, known mutations but lack the breadth of information provided by NGS.
Interpreting Results and Targeted Treatment Pathways
KRAS test results fall into two categories: “Wild-Type” or “Mutant.” A “Wild-Type” result indicates the KRAS gene in the tumor is normal, lacking an activating mutation. Patients with wild-type KRAS tumors are typically directed toward standard chemotherapy or further testing to find other actionable mutations.
A “Mutant” result means a specific alteration in the KRAS gene has been detected, and the report specifies the exact subtype, such as G12C or G12D. Identifying a mutation is now a direct pathway to targeted therapy, making KRAS an actionable target. The presence of a KRAS G12C mutation is significant because it allows for the use of specific, small-molecule inhibitors.
Targeted therapies like sotorasib (Lumakras) and adagrasib (Krazati) were developed to specifically and irreversibly inhibit the KRAS G12C mutant protein. These drugs covalently bind to a pocket on the altered protein, effectively locking it into the inactive, GDP-bound state and turning off the constant growth signal. Both sotorasib and adagrasib have received regulatory approval for treating patients with KRAS G12C-mutated NSCLC. Adagrasib is also approved for KRAS G12C-mutated CRC in combination with another drug. While these inhibitors have shown comparable effectiveness in NSCLC, with median progression-free survival rates of around six months, the choice between them depends on factors like side-effect profiles and adagrasib’s ability to penetrate the central nervous system.