Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. In a subset of these cancers, growth is driven by a specific genetic alteration known as the KRAS G12C mutation. The development of targeted drugs, called inhibitors, has provided a new and specific approach for patients with this mutation. These therapies are designed to counteract the effects of the G12C mutation, marking a step forward in personalized cancer treatment.
The Role of KRAS G12C in Lung Cancer
The KRAS protein in a healthy cell functions like a regulated switch, telling it when to grow and divide. The protein cycles between an “on” state to promote growth and an “off” state to stop these signals. This tightly controlled cycle is fundamental for preventing uncontrolled cell proliferation.
In some NSCLC patients, a mutation occurs where the glycine amino acid at position 12 is replaced by cysteine. This G12C mutation locks the KRAS protein permanently in the “on” position. This constant signal leads to uncontrolled cell division, a hallmark of cancer. The mutation is found in approximately 10-13% of patients with non-squamous NSCLC in Western countries.
For decades, the KRAS protein was considered “undruggable.” Its smooth, almost spherical shape lacks a conventional deep pocket where a drug could bind to disrupt its function. This structure made it difficult for researchers to design an effective small molecule, leaving chemotherapy as the primary option for these patients.
Mechanism of KRAS G12C Inhibitors
Scientists developed inhibitor molecules engineered to exploit the unique feature of the G12C mutation: the presence of a cysteine amino acid. These drugs are designed to fit into a shallow groove on the KRAS protein surface that appears only when the protein is in its inactive, “off,” state. Once the inhibitor is in this groove, it forms a strong, irreversible covalent bond with the sulfur atom of the cysteine.
This action can be compared to a key that not only fits a unique lock but permanently seals it shut. By binding directly to the mutated cysteine, the drug traps the KRAS G12C protein in its inactive conformation. This prevents the protein from sending the continuous growth signals that drive tumor proliferation, stopping the cancer’s growth at its source.
Approved Treatments and Their Efficacy
The U.S. Food and Drug Administration (FDA) has approved specific inhibitors for treating NSCLC with the KRAS G12C mutation. Two notable drugs in this class are sotorasib and adagrasib. These treatments are used for patients with advanced or metastatic NSCLC whose cancer has progressed after receiving other therapies.
For sotorasib, studies showed an objective response rate (ORR)—the percentage of patients whose tumors shrink significantly—of around 37%. The duration of response was a median of 11.1 months. Progression-free survival (PFS), the length of time before the cancer begins to grow again, was a median of 6.8 months.
Adagrasib produced an ORR of 42.9%, with a median progression-free survival of 6.5 months. Adagrasib also showed notable activity for patients with brain metastases, a common complication of advanced lung cancer. These metrics translate to meaningful periods where the tumor’s growth is controlled, providing patients with improved quality of life.
Managing Treatment and Potential Side Effects
While KRAS G12C inhibitors are effective, they are associated with potential side effects that require careful management. The most commonly reported issues are gastrointestinal, including diarrhea and nausea. Patients may also experience fatigue and musculoskeletal pain.
Another area of monitoring involves liver function, as these inhibitors can cause an increase in liver enzyme levels detectable through blood tests. Oncology teams monitor patients for signs of liver toxicity. They may adjust the dosage or temporarily pause treatment if necessary to allow the liver to recover.
Patients and caregivers should maintain open communication with their healthcare providers about any symptoms they experience. Early reporting allows for prompt intervention, which can often prevent side effects from becoming severe.
Overcoming Resistance and Future Outlook
A challenge in targeted cancer therapy is the development of acquired resistance. Over time, cancer cells can evolve new mutations or activate alternative signaling pathways to bypass the inhibitor, allowing the tumor to grow again. Researchers have observed this with KRAS G12C inhibitors as tumors find ways to reactivate growth signals.
To address this, research is focused on strategies to overcome or delay resistance, such as combination therapies. Clinical trials are investigating the effectiveness of pairing KRAS G12C inhibitors with treatments like chemotherapy, immunotherapy, or other targeted drugs. The rationale is that attacking the cancer from multiple angles may produce a more durable response and make it harder for resistance to develop.
The future of treatment also involves developing next-generation inhibitors designed to be more potent or to work against known resistance mechanisms. Research into biomarkers that can predict which patients are most likely to respond to treatment or develop resistance is also underway.