The KRAS gene provides instructions for a protein called K-Ras. This protein acts as a molecular switch, relaying signals that dictate cell growth and division. Its proper function is integral to maintaining normal cellular processes. When this gene undergoes changes, its altered function can contribute to various health conditions, particularly certain types of cancer.
The Normal Role of KRAS
The KRAS gene produces the K-Ras protein, which functions as a molecular switch within the RAS/MAPK pathway. This pathway transmits signals from outside the cell to its nucleus, instructing cells when to grow, divide, and develop into specialized cell types.
The K-Ras protein cycles between an “on” and “off” state. It is activated when it binds to a molecule called guanosine triphosphate (GTP) to relay signals. To turn off, the K-Ras protein converts GTP into guanosine diphosphate (GDP). This mechanism ensures that cell growth and division are tightly controlled.
When KRAS Goes Wrong
When the KRAS gene undergoes a mutation, its normal function as a molecular switch is disrupted. These mutations, such as G12C, G12D, or G12V, cause the K-Ras protein to become permanently “stuck in the on position.” This means the protein continuously sends signals for cell growth and division, even in the absence of external cues.
This continuous activation leads to uncontrolled cell proliferation. The mutated KRAS gene then acts as an oncogene, a gene that can cause normal cells to become cancerous. This sustained signaling contributes to the initiation and progression of various cancers by promoting unchecked cell growth and preventing programmed cell death.
KRAS and Cancer Treatment
Identifying KRAS mutations is important in cancer diagnosis and treatment planning. Historically, cancers driven by KRAS mutations have presented challenges for treatment, often showing resistance to conventional chemotherapy and some targeted therapies. This resistance stems from the constant activation of the K-Ras protein, which bypasses the mechanisms of many drugs.
Molecular testing, such as genomic sequencing, is used to detect these mutations in a patient’s tumor. The presence of a KRAS mutation can influence prognosis and guide therapeutic decisions, helping doctors understand how a tumor might behave and which treatments might be less effective. This allows for a more tailored approach to patient care.
Targeting KRAS
Breakthroughs have occurred in directly inhibiting mutated KRAS proteins. For decades, KRAS was considered an “undruggable” target due to its smooth surface and lack of obvious binding pockets. However, the development of specific inhibitors, such as those targeting the KRAS G12C variant, has transformed the treatment landscape.
These newer therapies offer a more precise approach to combat KRAS-driven cancers. For example, sotorasib was approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers with KRAS G12C mutations, based on clinical studies. While research continues for other KRAS subtypes and potential drug resistance, these direct inhibitors have opened new avenues for improving patient outcomes.