The c-kit gene is a proto-oncogene, a normal gene involved in cell growth and development. It provides instructions for making the C-KIT protein, also known as CD117 or the mast/stem cell growth factor receptor. This protein sits on the surface of cells, acting as a receiver for external signals. The C-KIT protein influences how cells grow, divide, and survive.
The Function of the C-KIT Protein
The C-KIT protein functions as a receptor tyrosine kinase. Its specific “key” is a signaling molecule called stem cell factor (SCF). When SCF binds to C-KIT, it triggers a change in the protein’s shape, sending signals into the cell’s interior. This process, known as signal transduction, activates pathways that regulate cell proliferation, survival, and differentiation.
C-KIT is found on various cell types in the body. These include hematopoietic stem cells, which form all types of blood cells, and mast cells, involved in allergic responses and immune regulation. C-KIT is also expressed on melanocytes, the cells that produce pigment, and on interstitial cells of Cajal (ICCs) in the digestive tract, which regulate gut movement.
C-KIT Mutations and Disease
When the c-kit gene undergoes mutations, its normal function can be disrupted, leading to disease. These are often “gain-of-function” mutations, meaning the C-KIT protein becomes permanently active, much like a light switch stuck in the “on” position. This continuous activation causes cells to grow and divide uncontrollably, even without the stem cell factor ligand. Such uncontrolled cell proliferation is a hallmark of cancer development.
Gastrointestinal Stromal Tumor (GIST), a type of soft tissue sarcoma affecting the digestive tract, is one of the most recognized diseases linked to c-kit mutations. Activating mutations in the c-kit gene are present in over 80% of GIST cases, making them a defining characteristic. These mutations frequently occur in exon 11 of the gene, which encodes a part of the protein that regulates its activity.
C-KIT mutations are also implicated in other conditions. Systemic mastocytosis, a rare disorder with excessive mast cell accumulation, is often driven by the specific c-kit mutation D816V, found in about 85-90% of adult cases. Certain types of acute myeloid leukemia (AML), a cancer of the blood and bone marrow, can also involve c-kit mutations. Additionally, some melanomas, a serious form of skin cancer, have been found to harbor c-kit alterations.
Diagnosing C-KIT Related Conditions
Doctors use specific methods to identify C-KIT involvement in various conditions, especially in cancer diagnosis. Immunohistochemistry (IHC) is a primary diagnostic technique. During this procedure, a pathologist examines a tissue sample, typically obtained through a biopsy, under a microscope. Special antibodies are applied to the tissue that bind specifically to the C-KIT protein.
If C-KIT is present, the antibodies will “stain” the cells, often with a visible color change, allowing confirmation of the protein’s presence and abundance. This staining helps confirm diagnoses like GIST, where C-KIT expression is detected in over 95% of cases. However, IHC alone may not always be sufficient to predict treatment response.
Genetic testing, also called mutational analysis, is often performed for a more precise understanding. This testing directly analyzes DNA from a tissue sample to identify specific c-kit gene mutations. Knowing the exact mutation type, such as those in exon 11 for GIST or D816V for mastocytosis, is important because different mutations can influence disease behavior and response to specific treatments.
Targeting C-KIT in Treatment
Understanding how mutated C-KIT drives uncontrolled cell growth has significantly advanced the treatment of several cancers, leading to “targeted therapies.” These therapies specifically interfere with the overactive C-KIT protein, rather than broadly attacking all rapidly dividing cells like traditional chemotherapy. The drugs used are called tyrosine kinase inhibitors (TKIs), which block the mutated C-KIT protein.
Imatinib (Gleevec) is a prominent TKI. It works by binding to the active site of the C-KIT protein, preventing it from sending growth signals inside the cell and stopping cancer cell proliferation. Imatinib has become the standard first-line treatment for advanced GIST, achieving objective responses in over 50% of patients and enabling long-term tumor control.
While imatinib is highly effective, resistance can develop over time, often due to secondary mutations in the c-kit gene. In such cases, other TKIs like sunitinib (Sutent) may be used as second-line treatments. Sunitinib is a multi-targeted TKI that can inhibit C-KIT along with other related kinases, offering an alternative when imatinib resistance occurs. The selection of a specific TKI can also depend on the particular c-kit mutation present, as some mutations respond differently to various inhibitors.