The KRAS gene is part of a protein family that acts as a switch in cellular signaling pathways controlling cell growth. When this gene mutates, it can become permanently “switched on,” leading to uncontrolled cell proliferation and cancer. In non-small cell lung cancer (NSCLC), KRAS mutations are one of the most frequent genetic drivers, present in about 30% of cases and are more common in individuals with a history of smoking.
For many years, the KRAS protein was labeled “undruggable” due to its spherical shape, which lacks deep pockets for a drug to bind and block its function. This structural challenge meant patients with KRAS-mutant lung cancer had limited treatment options and the mutation was associated with a poorer prognosis.
Targeted Therapies for the KRAS Mutation
Targeted therapy uses drugs designed to attack specific genetic abnormalities that fuel a tumor’s growth. For KRAS-mutant lung cancer, a breakthrough came with the development of drugs that address a specific variant known as KRAS G12C. Unlike chemotherapy, which affects all rapidly dividing cells, these therapies are more precise.
The discovery of a small, hidden pocket on the KRAS G12C protein’s surface enabled the creation of specific inhibitors like sotorasib and adagrasib. These drugs fit into this groove and lock the protein in an inactive state. This action prevents it from sending the constant “grow” signals that drive the cancer.
These inhibitors are prescribed for patients with advanced or metastatic KRAS G12C-mutant NSCLC whose cancer has progressed after a prior systemic therapy, like chemotherapy or immunotherapy. Clinical studies show these drugs can lead to tumor shrinkage and control the disease for a meaningful period. Common side effects include diarrhea, nausea, and fatigue, and are monitored by the oncology team.
Utilizing Immunotherapy
Immunotherapy is a treatment that harnesses a patient’s own immune system to fight cancer. A successful form for lung cancer involves immune checkpoint inhibitors, which work on immune cells called T-cells that are responsible for destroying threats. Cancer cells can produce proteins, like PD-L1, that act as a “brake” on the immune system, preventing T-cells from attacking the tumor.
Immune checkpoint inhibitors block this interaction, “releasing the brakes” and allowing the immune system to recognize and attack the cancer cells. This approach has transformed the treatment landscape for many types of advanced lung cancer.
For patients with KRAS-mutant NSCLC, immunotherapy combined with chemotherapy is a standard first-line treatment option. This strategy is not limited to the KRAS G12C subtype and can be effective for patients with other KRAS mutations. The presence of a KRAS mutation is associated with smoking, which can lead to more mutations in the tumor, making it more recognizable to the immune system.
The Place of Chemotherapy and Radiation
Traditional treatments like chemotherapy and radiation therapy continue to play a part in managing KRAS-mutant lung cancer. Chemotherapy uses drugs that kill rapidly dividing cells and is often used as a first-line treatment for advanced NSCLC in combination with an immune checkpoint inhibitor.
This combination can be effective because chemotherapy can cause cancer cells to die in a way that attracts the immune system, making the immunotherapy component more effective. This synergy is a cornerstone of initial treatment for many patients with advanced lung cancer, including those with KRAS mutations, before they might move on to a targeted therapy if their cancer progresses.
Radiation therapy is a localized treatment that uses high-energy rays to destroy cancer cells in a specific area. Its role is to treat the primary lung tumor directly or to manage symptoms by targeting metastases—areas where the cancer has spread. For instance, radiation can be used to shrink tumors in the brain or bones to alleviate pain and improve a patient’s quality of life.
Exploring Clinical Trials
Clinical trials are research studies that test new treatments or new ways of using existing ones. They are an important part of advancing cancer care and offer patients access to the next generation of therapies. For patients with KRAS-mutant lung cancer, clinical trials are an important avenue as the field is evolving rapidly.
While approved targeted therapies exist for the KRAS G12C mutation, they do not yet exist for other common KRAS variants like G12D or G12V. For patients with these non-G12C mutations, clinical trials are the primary way to access novel drugs designed to inhibit their type of KRAS mutation. These trials are investigating a new wave of inhibitors that aim to target these other variants.
Clinical trials are also exploring innovative strategies to improve outcomes for all KRAS patients. This includes testing new combinations, such as pairing a KRAS inhibitor with an immune checkpoint inhibitor or other targeted drugs. The goal is to create a more durable response and overcome treatment resistance. Patients interested in learning about clinical trials should speak with their oncologist, who can help identify appropriate studies.