The MAPK pathway is a chain of proteins inside cells that carries growth signals from the cell surface to its control center, the nucleus. Its name stands for mitogen-activated protein kinase, and it is also called the RAS-RAF-MEK-ERK pathway after the main proteins involved. The MAPK pathway is a normal part of how healthy cells function, signaling when to grow, divide, and survive. It usually switches on only when needed and then turns off again. The term often appears in a pathology report when a genetic change (mutation) affecting this pathway has been found in a tumor.
This article explains what the MAPK pathway is and why it may be mentioned in your pathology report.
What does the MAPK pathway do?
The MAPK pathway works like a relay, passing a message from one protein to the next. A signal from outside the cell activates a protein called RAS, which switches on RAF (one form of which is called BRAF), which then activates MEK, which activates ERK. When ERK reaches the nucleus, it turns on the genes that tell the cell to grow and divide. In a healthy cell, this relay runs only when the body needs new cells and then shuts off. This careful control keeps cell growth in balance.
Why does the MAPK pathway matter in cancer?
Many cancers develop when a mutation in one of the genes in the MAPK pathway causes it to stay switched on all the time. When this happens, the cell receives a constant signal to grow and divide, even when it should not, which can lead to a tumor. Genes in this pathway that are commonly altered in cancer include BRAF, KRAS, NRAS, and MAP2K1 (also called MEK). Changes in the MAPK pathway are found across many types of cancer, including melanoma, colorectal cancer, thyroid cancer, and lung cancer, as well as in histiocytic disorders such as Langerhans cell histiocytosis and Erdheim-Chester disease.
How is the MAPK pathway tested?
The MAPK pathway itself is not measured directly. Instead, the laboratory looks for mutations in the genes that make up the pathway. This is usually done with molecular tests such as next-generation sequencing, which can examine many genes at once, or with a targeted test for a single change. In some cases, a special immunohistochemistry stain can detect a specific altered protein, such as BRAF V600E, directly in the tissue. The result is usually reported by naming the gene and the specific change that was found, such as BRAF V600E, and describing it as present (positive) or not detected (negative).
How does the MAPK pathway affect treatment?
Finding a mutation in the MAPK pathway can be important because medicines have been developed to block specific steps in the signaling cascade. BRAF inhibitors block an overactive BRAF protein, and MEK inhibitors block the MEK protein further along the pathway. When a tumor is driven by a MAPK pathway mutation, these targeted drugs may be an option, sometimes used together. Identifying a mutation in this pathway, therefore, helps the treatment team decide whether targeted therapy is likely to be effective. You can read more in the Biomarkers and Genetic Testing section.
Questions to ask your doctor
- Was a mutation in the MAPK pathway found in my tumor?
- Which gene was affected, and what was the specific change?
- How was the testing performed?
- Does this result make me eligible for targeted therapy, such as a BRAF or MEK inhibitor?
- Could this result have any implications for my treatment options or prognosis?
- Are there clinical trials related to this pathway that I should consider?
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