The KRAS gene is one of the most frequently mutated oncogenes found in human cancers. As a member of the RAS family, alterations to this gene are implicated in a substantial proportion of new cancer diagnoses globally. Understanding the function of the normal KRAS protein and how its mutation drives uncontrolled cell growth is necessary for developing effective, personalized cancer treatments.
The KRAS Gene and Cellular Signaling
The protein encoded by the KRAS gene is a small GTPase, functioning as a molecular switch for the cell. This protein relays signals from cell surface receptors to the nucleus, instructing the cell on how to behave. In its normal state, KRAS cycles between two conformations: an active “on” state and an inactive “off” state.
The “on” state occurs when KRAS is bound to Guanosine Triphosphate (GTP). When bound to GTP, KRAS activates downstream cascades, such as the Mitogen-Activated Protein Kinase (MAPK) pathway, which promote cell proliferation, growth, and survival. The protein possesses an intrinsic enzymatic ability to convert GTP into Guanosine Diphosphate (GDP), which flips the switch to the “off” state. This conversion is a tightly controlled process, ensuring that the cell only grows and divides when necessary.
When KRAS Becomes a Cancer Driver
A mutation in the KRAS gene disrupts the protein’s ability to convert GTP to GDP, essentially breaking the “off” switch. This structural change locks the KRAS protein in its active, GTP-bound state, leading to continuous and unregulated signaling to the nucleus. The constant activation of growth pathways, such as MAPK, results in uncontrolled cell division and the formation of a malignant tumor.
These activating mutations occur at specific locations, most commonly at codons 12, 13, and 61. The specific amino acid substitution determines the mutation subtype, with G12C, G12D, and G12V being the most prevalent forms across all cancers. Cancers commonly driven by a KRAS mutation include Pancreatic Ductal Adenocarcinoma (up to 96% of cases), Colorectal Cancer (30% to 40% incidence), and Non-Small Cell Lung Cancer (NSCLC), affecting 30% to 40% of patients.
Detecting KRAS Mutations in Patients
Identifying the specific KRAS mutation is necessary for treating patients, as it acts as a predictive biomarker for targeted therapy. Molecular profiling is typically performed on a tumor tissue sample obtained through a biopsy. Techniques like Next-Generation Sequencing (NGS) are widely used to analyze the DNA, allowing for the precise identification of the mutated gene and the exact amino acid substitution.
When a tissue biopsy is not feasible, a minimally invasive alternative called a liquid biopsy can be used. This test analyzes circulating tumor DNA (ctDNA) released by cancer cells into the bloodstream. Highly sensitive methods, such as droplet digital Polymerase Chain Reaction (ddPCR), are employed to detect the low levels of mutant DNA in the blood sample. Identifying the specific subtype, such as G12C versus G12D, is important because treatment effectiveness can vary significantly depending on the exact mutation present.
New Horizons in Targeted KRAS Therapy
For decades, KRAS was considered “undruggable” due to its smooth surface structure and high affinity for GTP, which made it difficult for drugs to bind and inhibit its function. This challenge persisted until researchers discovered a unique, shallow pocket present only in the GDP-bound, inactive state of the G12C mutant protein. This discovery marked a turning point, providing a structural opportunity for therapeutic intervention.
The breakthrough led to the development and approval of the first direct KRAS G12C inhibitors, such as sotorasib and adagrasib. These agents work by forming a permanent, covalent bond with the unique cysteine residue introduced by the G12C mutation. This binding effectively locks the KRAS protein into its inactive, GDP-bound conformation, preventing the activation of downstream cancer-promoting pathways. The success of these G12C-specific inhibitors has validated the strategy of directly targeting KRAS.
While G12C inhibitors are revolutionary, they only benefit patients with that specific subtype. The majority of patients with KRAS-driven cancers, particularly those with G12D or G12V mutations prevalent in pancreatic and colorectal cancers, still lack an approved direct inhibitor. Research is intensely focused on developing therapeutic agents for these other common variants, with several promising G12D-specific inhibitors currently advancing through clinical trials. Furthermore, combination therapies are being explored to overcome treatment resistance, pairing KRAS inhibitors with agents that block parallel signaling pathways like PI3K-AKT or MEK, in an effort to achieve more durable and widespread clinical responses.