A biomarker is a molecule found in blood, body fluids, or tissues that provides information about a person’s medical state. In cancer care, biomarkers can indicate a cancer’s aggressiveness or which treatments are most likely to work. One of the most significant is related to the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene.
The KRAS gene provides instructions for making a protein called K-Ras, part of a signaling pathway that controls cell growth. When the KRAS gene mutates, it can become a driver of cancer by causing cells to multiply uncontrollably. These mutations are not inherited but are acquired during a person’s lifetime and are found only in tumor cells. Understanding the KRAS biomarker is important for diagnosing and treating several major cancer types.
The Role of the KRAS Gene in Cell Growth
The KRAS gene is a member of a family of genes known as oncogenes. In their normal, unmutated state, these genes produce proteins that manage cellular functions like proliferation and differentiation. The K-Ras protein acts like a molecular “on/off switch,” relaying signals from outside the cell to the nucleus to control when the cell should grow and divide. To transmit these signals, the protein must be turned on by binding to a molecule called guanosine triphosphate (GTP).
When a cell receives external growth factor signals, these are passed through a chain of command that activates the K-Ras protein. Once bound to GTP, the active K-Ras protein triggers several downstream signaling cascades, most notably the RAF-MEK-ERK and PI3K-AKT pathways. These pathways execute the commands for cell cycle progression and survival. After the signal is delivered, the K-Ras protein converts GTP to guanosine diphosphate (GDP), which flips the switch to the “off” position, halting the growth signal.
A mutation in the KRAS gene causes the K-Ras protein to become stuck in the “on” position, continuously bound to GTP. This leads to the constant activation of growth pathways, even without external signals. The cells receive an unchecked command to proliferate, which can lead to the formation of tumors. This constant signaling is why mutated KRAS functions as an oncogene.
Identifying KRAS Mutations in Patients
Detecting a KRAS mutation is a standard part of the diagnostic process for several cancers, especially for patients with metastatic disease. The most established method is a tissue biopsy, where a small sample of the tumor is surgically removed for laboratory analysis. Technicians perform genomic testing, such as next-generation sequencing (NGS), to scan for mutations in cancer-related genes, including KRAS, providing a profile of the tumor’s genetics.
A newer, less invasive method is the liquid biopsy, which requires only a blood sample. Tumors shed fragments of their DNA, known as circulating tumor DNA (ctDNA), into the bloodstream. A liquid biopsy detects and analyzes this ctDNA to identify specific mutations like those in the KRAS gene. This method is useful when a tissue biopsy is not feasible due to the tumor’s location or the patient’s health.
A tissue biopsy is considered the gold standard because it directly analyzes the tumor cells, providing a large amount of DNA for a detailed assessment. Liquid biopsies are simpler to perform, carry fewer risks, and can be repeated over time to monitor how a tumor’s genetic profile changes in response to treatment. Studies have shown a high rate of agreement between the two methods, making both valuable tools in clinical practice.
KRAS as a Prognostic and Predictive Biomarker
Once a KRAS mutation is identified, it serves two distinct roles for oncologists: as a prognostic and a predictive biomarker. These functions are different but equally important in guiding a patient’s care plan.
As a prognostic biomarker, a KRAS mutation provides insight into the cancer’s likely course and aggressiveness, regardless of treatment. Tumors with a KRAS mutation are associated with a poorer prognosis compared to tumors without one. For example, in non-small cell lung cancer (NSCLC), patients with KRAS mutations have shorter overall survival times than patients with wild-type (unmutated) KRAS and EGFR genes.
As a predictive biomarker, a KRAS mutation forecasts how a tumor will respond to specific treatments. Historically, this was a negative prediction; a KRAS mutation in metastatic colorectal cancer indicates non-response to EGFR inhibitors, preventing patients from receiving an ineffective treatment. More recently, the predictive role has become positive, as the identification of a specific mutation like G12C predicts a likely response to a new class of targeted drugs.
Targeted Therapies for KRAS-Mutant Cancers
For decades, the KRAS protein was considered “undruggable.” Its smooth surface lacked obvious pockets where a drug could bind, and its powerful affinity for the GTP molecule made it nearly impossible to block its activation. This posed a challenge for researchers and left patients with KRAS-mutant cancers, which account for about 25% of all solid tumors, with fewer treatment options for cancers like lung, colorectal, and pancreatic cancer.
This landscape began to change with a discovery in 2013. Scientists identified a structural feature in one of the most common KRAS mutants, known as G12C. This mutation substitutes a glycine amino acid with a cysteine, creating a small pocket that a specially designed molecule could latch onto. This breakthrough paved the way for developing drugs that could directly target the mutant KRAS protein, turning the “undruggable” into the druggable.
The first of these targeted drugs, sotorasib and adagrasib, received FDA approval following clinical trials. These oral medications work by irreversibly binding to the cysteine in the KRAS G12C protein, locking it in its inactive, GDP-bound state. This action shuts down the signaling pathways that drive cell proliferation. These inhibitors are now used to treat patients with KRAS G12C-mutated non-small cell lung cancer and colorectal cancer, typically after other treatments have stopped working.
The success of KRAS G12C inhibitors has ignited a new wave of research. Scientists are now developing therapies that can target other common KRAS mutations, such as G12D and G12V, which have different structural properties. Clinical trials are exploring novel inhibitors for these mutations, as well as combination strategies that pair KRAS inhibitors with other therapies to improve outcomes. This ongoing work suggests a future where more KRAS-mutant cancers can be treated with precision medicine.