KRAS mutations are changes in the KRAS gene, a specific segment of DNA within our cells. These genetic alterations are common and significant in human health, often found in many human tumors.
The Normal Function of KRAS
The KRAS gene provides instructions for creating the K-Ras protein, which functions as a molecular switch within cells. This protein is a component of the RAS/MAPK pathway, a signaling network that relays messages from outside the cell to its nucleus. These signals direct fundamental cellular processes, including growth, division, and maturation.
The K-Ras protein operates by binding to guanosine triphosphate (GTP), which turns the switch “on” to transmit signals. To turn “off” and stop signaling, it converts GTP into guanosine diphosphate (GDP). This on-off mechanism ensures tightly regulated cell behavior, maintaining normal cellular functions.
How KRAS Mutations Lead to Cancer
A mutation in the KRAS gene alters the K-Ras protein, causing it to become persistently active, or “stuck in the on position.” This continuous activation leads to uncontrolled cell growth and division, a hallmark of cancer. The KRAS gene belongs to a class of genes known as oncogenes, which can transform normal cells into cancerous ones when mutated.
These mutations can also cause chromatin rearrangements within cells, reverting tissue cells to an early developmental or “stem-like” state, initiating tumor formation. KRAS mutations are notably prevalent in several cancer types, driving approximately 32% of lung cancers, 40% of colorectal cancers, and 85% to 90% of pancreatic cancer cases. The most common KRAS mutations found in cancers are G12C, G12D, and G12V.
Diagnosing KRAS Mutations
Detecting KRAS mutations in patients is achieved through molecular testing, which helps guide personalized treatment strategies. One common method involves analyzing tissue from a tumor biopsy. This tissue is subjected to next-generation sequencing (NGS), a technique that simultaneously scans for many biomarkers, including mutations, across numerous cancer-related genes.
When a tissue biopsy is not feasible, a liquid biopsy may be recommended. This method involves analyzing a patient’s blood to detect circulating tumor DNA (ctDNA), which can carry genetic mutations from cancer cells. Liquid biopsies can accurately identify molecular alterations, offering a less invasive option for diagnosis and monitoring. These tests are important for understanding the specific genetic makeup of a tumor, which influences treatment decisions.
Targeted Therapies for KRAS Mutations
Targeting KRAS mutations has historically been challenging due to the protein’s small size and smooth surface, which lacks deep pockets for drugs to bind effectively. However, recent advancements have led to the development of specific targeted therapies, particularly for the KRAS G12C mutation. These new drug classes, known as G12C inhibitors, work by selectively binding to the mutated cysteine at position 12 in the K-Ras protein when it is in its inactive, GDP-bound state, locking it in this non-signaling form.
Sotorasib and adagrasib are two G12C inhibitors that have demonstrated efficacy in clinical trials, particularly for non-small cell lung cancer (NSCLC) patients with the KRAS G12C mutation who have received prior treatments. Sotorasib received accelerated approval for this patient group. These therapies represent a significant step in precision medicine, where treatments are tailored to the specific genetic alterations within a patient’s tumor, improving outcomes. Research continues into additional KRAS inhibitors and combination therapies to address other KRAS mutation subtypes and overcome potential drug resistance mechanisms.