The KRAS protein is a small guanosine triphosphatase (GTPase) that plays a fundamental role in cellular communication. It transmits signals from outside the cell to its interior, influencing various cellular activities. When functioning properly, KRAS contributes to the regulated growth and development of cells.
KRAS in Healthy Cells
In healthy cells, the KRAS protein functions much like a molecular switch, carefully regulating cellular responses to external stimuli. It cycles between an active “on” state when bound to GTP and an inactive “off” state when bound to GDP. Growth factors or other signaling molecules bind to receptors on the cell surface, initiating a cascade that leads to KRAS becoming active. This activation allows KRAS to transmit signals downstream, influencing pathways that govern cell growth, division, and survival.
Once its signaling role is complete, KRAS hydrolyzes GTP to GDP, returning to its inactive state and effectively turning off the signal. This precise on-off switching mechanism ensures that cells only grow and divide when appropriate signals are present. For instance, after receiving a signal for growth, KRAS activates pathways such as the MAPK (mitogen-activated protein kinase) and PI3K (phosphatidylinositol 3-kinase) pathways. These pathways then relay the signal further into the cell nucleus, where they modulate gene expression related to proliferation and survival. Its ability to revert to an inactive state prevents continuous, unchecked signaling, maintaining cellular equilibrium.
When KRAS Goes Awry
Mutations within the KRAS gene can disrupt its normal regulatory mechanism, leading to a protein that remains persistently in its active “on” state. These genetic alterations, often occurring at specific amino acid positions like G12, G13, or Q61, prevent KRAS from hydrolyzing GTP to GDP effectively. As a result, the mutant KRAS protein continuously sends growth and survival signals, even in the absence of external stimuli. This constant activation bypasses the natural cellular controls designed to prevent excessive proliferation.
The sustained signaling from mutant KRAS promotes uncontrolled cell growth and division, a hallmark characteristic of cancer development. Cells with an “always on” KRAS protein can accumulate additional genetic changes, further contributing to their cancerous transformation. This dysregulation leads to the formation of tumors and can contribute to the metastatic spread of cancer throughout the body.
Identifying KRAS Mutations
Detecting KRAS gene mutations in patients is a standard procedure in oncology, guiding treatment decisions. These mutations are typically identified through molecular tests performed on tissue samples obtained from tumor biopsies. Pathologists and molecular biologists analyze these samples to pinpoint the exact genetic alterations. The specific location of the mutation, such as G12C or G12D, is often identified.
Liquid biopsies, which involve analyzing a blood sample for circulating tumor DNA (ctDNA), offer another method for detecting KRAS mutations. This less invasive approach can provide information about the tumor’s genetic profile without the need for a tissue biopsy. Identifying these mutations helps clinicians understand the underlying biology of a patient’s cancer, allowing for a more tailored approach to therapy. The presence of a KRAS mutation can influence the choice of drugs or indicate eligibility for specific clinical trials.
Therapeutic Strategies for KRAS
For many years, directly targeting the KRAS protein was considered challenging due to its smooth, featureless surface, making it difficult for drugs to bind effectively. This led to KRAS being dubbed “undruggable” by some researchers. However, recent scientific advancements have led to the development of molecules that can specifically inhibit certain KRAS mutations. These breakthroughs have reshaped the landscape of cancer treatment for patients with KRAS-mutated tumors.
One significant development involves direct KRAS G12C inhibitors, such as sotorasib and adagrasib. These drugs work by forming a covalent bond with the mutant KRAS G12C protein, locking it into an inactive GDP-bound state. This action effectively “turns off” the constitutively active protein, thereby halting the uncontrolled growth signals that drive cancer progression. These inhibitors have demonstrated clinical benefit in patients with specific KRAS G12C-mutated cancers, particularly in non-small cell lung cancer.
Building on the success of direct inhibitors, research continues into other strategies, including targeting different KRAS mutations beyond G12C. Combination therapies, which involve using a KRAS inhibitor alongside other targeted agents or chemotherapy, are also being explored. These approaches aim to overcome potential resistance mechanisms and enhance treatment efficacy by simultaneously blocking multiple pathways that cancer cells exploit. The ongoing development of these therapeutic strategies offers new possibilities for patients with KRAS-driven cancers.