Lung cancer remains a significant health challenge globally, and its treatment landscape has shifted considerably with the understanding of molecular drivers. These specific genetic changes within a tumor guide therapeutic decisions, moving away from a one-size-fits-all approach. The KRAS mutation has long been recognized as one of the most common, yet historically the most difficult to treat directly. The recent emergence of targeted treatments represents a major shift, transforming the prognosis for a distinct subgroup of patients.
Understanding the KRAS Mutation in Lung Cancer
The KRAS gene is responsible for producing a protein that acts as a molecular switch, regulating cell growth, division, and survival. In a healthy cell, this protein cycles between an active state, where it signals for growth, and an inactive state, where it rests. Mutations in the gene, which occur in approximately 25% of non-small cell lung cancers (NSCLC), disrupt this normal cycling.
The mutation essentially jams the switch in the “on” position, similar to a car’s accelerator pedal being permanently stuck down. This constant signal drives the uncontrolled proliferation that defines cancer. For decades, the KRAS protein was considered “undruggable” due to its smooth, featureless structure, which prevented the design of drugs that could effectively bind to and block its activity.
The most common variant in NSCLC is KRAS G12C, accounting for about 40% of all KRAS mutations in lung tumors. This specific G12C change—where the amino acid glycine is replaced by cysteine at position 12—creates a unique pocket on the protein surface that scientists have finally learned to exploit.
Molecular Testing for KRAS
Determining the presence and specific type of a KRAS mutation is a mandatory first step before any treatment can be planned. This process, known as molecular profiling, is performed on tumor tissue obtained through a biopsy or, in some cases, via a liquid biopsy. A liquid biopsy analyzes fragments of tumor DNA circulating in the blood, offering an alternative when a tissue sample is insufficient or difficult to obtain.
The testing method most often recommended is Next-Generation Sequencing (NGS), which can simultaneously identify multiple actionable biomarkers, including the entire spectrum of KRAS variants. Identifying the precise variant is essential because only the KRAS G12C subtype currently has approved targeted therapies. While KRAS G12V and G12D are also common, they do not respond to the G12C-specific drugs and require a different treatment strategy. The results of this comprehensive testing must be available quickly, as they directly dictate the most effective therapeutic path.
Targeted Therapies: The Rise of KRAS Inhibitors
The breakthrough in KRAS treatment centers on a new class of drugs designed specifically to target the unique cysteine residue in the G12C mutant protein. These targeted inhibitors represent a major paradigm shift, moving KRAS from an untouchable oncogene to an actionable target. Two such inhibitors, sotorasib and adagrasib, have received regulatory approval for treating KRAS G12C-mutated NSCLC.
Both sotorasib and adagrasib function by binding irreversibly to the KRAS G12C protein. This binding locks the mutant protein into its inactive, GDP-bound state, effectively preventing it from sending the continuous growth signals. By trapping the protein in this “off” conformation, the drugs halt the downstream signaling pathways that promote cell proliferation.
These inhibitors are administered orally. Clinical trials have established that these oral medications provide meaningful clinical benefits for patients with advanced disease who have previously received systemic therapy. The most common side effects are generally manageable and include gastrointestinal issues such as diarrhea and nausea, fatigue, and musculoskeletal pain. Sotorasib was the first KRAS G12C inhibitor to receive accelerated approval, followed shortly by adagrasib.
Standard Systemic and Local Treatments
Not all patients with a KRAS mutation are candidates for the G12C-specific targeted therapies. Those with other KRAS variants, such as G12D or G12V, or those diagnosed before targeted options were established, rely on established treatment modalities. These standard treatments remain an important part of the overall strategy for KRAS-positive NSCLC.
Systemic treatments often include platinum-based chemotherapy regimens, which work by killing rapidly dividing cells. Immunotherapy, typically involving PD-1 or PD-L1 inhibitors, is another standard approach for many NSCLC patients. These agents harness the body’s own immune system to recognize and attack cancer cells, and they can be particularly effective in some KRAS-mutant tumors.
For patients with localized disease, local treatments like surgery and radiation therapy play a significant role. Surgery may be performed to remove the tumor entirely, and radiation uses high-energy rays to destroy cancer cells. These modalities are often used in combination with systemic therapy, depending on the stage and extent of the cancer.
In contemporary practice, these standard treatments are frequently used in sequence or combination with the KRAS inhibitors. For example, chemotherapy or immunotherapy may serve as the first-line treatment for non-G12C KRAS variants, providing essential therapeutic options while research continues to develop targeted drugs for the remaining KRAS subtypes.
Addressing Resistance and Emerging Strategies
A challenge with any targeted therapy is the eventual development of treatment resistance, and KRAS inhibitors are no exception. Over time, tumor cells can adapt, finding new ways to bypass the drug’s effect and resume growth. Mechanisms of resistance can be categorized as on-target, such as a new KRAS mutation that prevents drug binding, or off-target, involving the activation of alternative signaling pathways.
To overcome this, a major focus of current research is combination therapy. Scientists are exploring combining KRAS G12C inhibitors with other targeted agents, such as MEK or SHP2 inhibitors, to block multiple growth signals simultaneously. Combining KRAS inhibitors with immunotherapy is also under investigation, aiming for a synergistic effect that attacks the tumor from two different directions.
Furthermore, research efforts are intensely focused on developing drugs that can target the non-G12C KRAS variants, which currently lack approved targeted options. This includes the development of pan-KRAS inhibitors, designed to block multiple different KRAS mutations, including G12D and G12V. These emerging strategies offer the potential to provide tailored and durable treatment options for all patients with KRAS-mutated lung cancer.