KIT inhibitors are a form of targeted therapy, a precision approach designed to act on specific molecules involved in the growth of abnormal cells. These drugs interact with a particular molecular target that drives a disease, allowing for a more focused attack on malfunctioning cells. This method aims to minimize damage to healthy tissues and is used for conditions where the target molecule plays a central role.
The Role of the KIT Protein
The KIT protein is a receptor tyrosine kinase found on the surface of various cells. Its primary job is to receive signals from a substance called stem cell factor (SCF). When SCF binds to the KIT protein, it activates a chain of events inside the cell called signal transduction. This signaling controls cellular activities like growth, division, and survival, and is important for the normal development of blood cells, melanocytes, and interstitial cells of Cajal (ICCs).
The instructions for building the KIT protein are encoded in the KIT gene. Mutations in this gene can result in a KIT protein that is structurally altered and becomes permanently “switched on,” even without receiving a signal from SCF. This state of constant activation is referred to as constitutive activation.
This relentless signaling leads to uncontrolled cell proliferation and survival. Specific gain-of-function mutations in the KIT gene are identified as drivers in several types of cancer, including gastrointestinal stromal tumors (GISTs), certain leukemias, and melanoma. The malfunctioning protein continuously sends growth signals, compelling cells to multiply and form tumors.
Mechanism of Action
KIT inhibitors are small-molecule drugs engineered to halt the activity of the mutated KIT protein. Their design allows them to fit into the ATP-binding pocket. Adenosine triphosphate (ATP) provides the energy for the kinase to function; by occupying this pocket, the inhibitor prevents ATP from binding. This action effectively blocks the protein’s ability to send downstream signals.
By blocking this specific site, the inhibitor shuts down the constant “on” signal that the mutated KIT protein generates. This interruption of the signaling cascade stops cancer cells from growing and dividing uncontrollably. Some inhibitors are designed to bind to the protein when it is in an inactive shape, while others can bind to its active form, which is relevant for targeting different types of mutations.
This targeted approach distinguishes these inhibitors from traditional chemotherapy. Rather than affecting all rapidly dividing cells, they are designed to act on cells dependent on the faulty KIT signaling pathway for their survival and proliferation. The result is a more direct and focused therapeutic effect on the cancer itself.
Medical Applications
The primary medical use for KIT inhibitors is in the treatment of Gastrointestinal Stromal Tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract. Over 80% of GISTs are driven by activating mutations in the KIT gene. The first successful drug in this class, imatinib, is a standard first-line therapy for advanced or inoperable cases. Following imatinib, other inhibitors like sunitinib and regorafenib were developed as second- and third-line treatments for patients whose tumors become resistant.
Another significant application is in the management of Systemic Mastocytosis (SM), a rare disorder characterized by the excessive accumulation of mast cells in various tissues. A specific mutation, KIT D816V, is the primary driver in over 90% of SM cases. Because this mutation makes the cancer resistant to imatinib, other inhibitors were developed. Midostaurin and avapritinib are designed to be effective against this D816V mutation and are used to treat advanced forms of the disease.
Certain types of Acute Myeloid Leukemia (AML) also involve mutations in the KIT gene. While less common than in GIST or SM, these mutations can contribute to the development of this blood and bone marrow cancer. Midostaurin, which targets a broad spectrum of kinases including KIT, is approved for use in combination with chemotherapy for AML patients who have a specific FLT3 mutation, another type of kinase often affected alongside KIT.
Common Side Effects
Patients taking KIT inhibitors may experience side effects because these drugs can affect the normal KIT protein in healthy cells or other similar kinase proteins. It is important for patients to communicate all side effects to their healthcare provider, as there are often strategies to manage them. Common side effects include:
- Fluid retention (edema), which can manifest as swelling in the hands, feet, and puffiness around the eyes.
- Gastrointestinal problems, such as nausea, diarrhea, and abdominal pain.
- Fatigue, a persistent feeling of tiredness or lack of energy that is not relieved by rest.
- Skin reactions, which can range from a mild rash to more pronounced skin changes.
Drug Resistance and Treatment Progression
A challenge in the long-term use of KIT inhibitors is the development of drug resistance, where the treatment loses its effectiveness over time. Primary resistance is when the drug is ineffective from the beginning, often because the specific KIT mutation present in the tumor is not susceptible to the inhibitor being used. For instance, the KIT D816V mutation common in systemic mastocytosis confers primary resistance to imatinib.
Secondary, or acquired, resistance happens after an initial period of successful treatment. The cancer cells can evolve and develop new mutations within the KIT gene that prevent the drug from binding effectively. These secondary mutations often occur in different parts of the protein, such as the ATP-binding pocket or activation loop, altering its shape and rendering the initial inhibitor useless.
To combat this, a strategy of sequential therapy is often employed. When a patient develops resistance to a first-line inhibitor like imatinib, they may be switched to a second-line drug, such as sunitinib, which is designed to be effective against some of the common secondary mutations. If resistance develops again, a third-line option like regorafenib or a broader-spectrum inhibitor like ripretinib may be used.