KRAS inhibitors are a new class of drugs representing an advancement in targeted cancer therapy. These medications counteract one of the most common and challenging drivers of tumor growth. For decades, the protein from a mutated KRAS gene was considered “undruggable” due to its molecular structure. The development of KRAS inhibitors provides a method for shutting down this persistent growth signal, offering a precision approach for difficult-to-treat cancers.
The KRAS Gene and Its Role in Cell Growth
The KRAS gene provides instructions for making the K-Ras protein, a component of the RAS/MAPK signaling pathway. This pathway acts as a communication network, relaying signals from the cell’s exterior to its nucleus. These messages direct the cell to perform functions like growing, dividing, or maturing into specialized cell types.
The K-Ras protein functions like a regulated molecular switch. To transmit signals, the K-Ras protein must be turned on by binding to a molecule called GTP and is turned off when it converts GTP into another molecule, GDP. In its “off” state, bound to GDP, the protein does not send growth signals. This on-and-off cycling is a controlled part of a cell’s life, ensuring cell division happens only when needed.
KRAS Mutations as a Driver of Cancer
When the KRAS gene mutates, its protein product can become stuck in the “on” position. This change disrupts the normal signaling cycle, leading to a protein that is constantly active and sending unrelenting growth signals to the cell’s nucleus. This malfunction causes cells to grow and divide uncontrollably, a characteristic of cancer. These genetic changes, known as somatic mutations, are acquired during a person’s lifetime and are present only in tumor cells.
KRAS mutations are a common genetic driver in human cancers, appearing in about a quarter of all tumors. They are particularly prevalent in some of the most aggressive and difficult-to-treat cancers. KRAS mutations are found in 85% to 90% of pancreatic cancer cases, 40% of colorectal cancers, and 32% of non-small cell lung cancers (NSCLC). The presence of these mutations is associated with a poorer prognosis and resistance to certain cancer therapies.
Mechanism of KRAS Inhibitors
The breakthrough in targeting KRAS came with inhibitors for a specific mutation, KRAS G12C. In this mutation, the amino acid glycine at position 12 is replaced by cysteine, creating a unique groove on the protein’s surface. This structural change provided the foothold necessary for a drug to attach.
KRAS inhibitors are designed to fit into this newly formed pocket on the mutated protein. These drugs work by forming a covalent bond with the cysteine residue, which irreversibly locks the KRAS G12C protein in its inactive, GDP-bound state. By trapping the protein in the “off” position, the inhibitor prevents it from sending the continuous growth signals that drive tumor proliferation. This mechanism silences the mutated protein, shutting down downstream signaling pathways, like the MAPK pathway, responsible for uncontrolled cell growth.
Current KRAS Inhibitor Therapies
Targeting the KRAS G12C mutation has led to the FDA approval of inhibitor therapies like sotorasib and adagrasib. Sotorasib is approved for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with the KRAS G12C mutation who have received prior systemic therapy. It is also approved in combination with another drug for metastatic KRAS G12C-positive colorectal cancer after previous chemotherapy.
Adagrasib has a similar indication for adult patients with KRAS G12C-mutated advanced or metastatic NSCLC who have undergone prior systemic therapy. Both treatments have demonstrated clinical responses in patients whose tumors harbor this specific mutation. Common side effects associated with these inhibitors include:
- Diarrhea
- Musculoskeletal pain
- Nausea
- Fatigue
- Potential liver toxicity
Patients are closely monitored for these effects, particularly for changes in liver enzyme levels and for a rare but serious side effect known as interstitial lung disease or pneumonitis.
Expanding the Scope of KRAS Inhibition
The success of drugs targeting the KRAS G12C mutation confirmed KRAS is a druggable target, spurring research into inhibitors for other KRAS mutations. The G12C mutation is just one of several variants; other common mutations include G12D and G12V, which are prevalent in aggressive cancers like pancreatic and colorectal cancer. These mutations present different challenges because they do not have the same cysteine residue that G12C inhibitors exploit.
Researchers are exploring strategies to target these other mutations. For example, a noncovalent inhibitor, MRTX1133, is being developed to target the KRAS G12D mutation and is in early-phase clinical trials. Other approaches include developing pan-RAS inhibitors, which are designed to work against multiple types of RAS mutations, not just KRAS. The goal is to broaden the range of patients who can benefit from this type of targeted therapy, extending the success seen with G12C inhibitors to more KRAS-mutated cancers.