The BRAF/MEK Pathway in Cancer and Targeted Therapy

Cells in the human body are in constant communication, receiving instructions that tell them when to grow, when to divide, and when to stop. This communication occurs through internal signaling pathways, which function much like a relay race. An initial signal from outside the cell is passed from one specialized protein to another until it reaches its final destination, usually the cell’s nucleus, to trigger a specific action.

Dozens of these routes operate simultaneously to ensure cellular activities are orderly. One of these is the BRAF/MEK pathway, a chain of command that translates external cues into instructions for normal cell growth and survival.

How the Pathway Functions in Healthy Cells

The signaling process in a healthy cell begins when a specific molecule, such as a growth factor, binds to a receptor on the cell’s outer surface. This activates the receptor, which in turn switches on a protein inside the cell called RAS. Once activated, RAS recruits a protein kinase known as BRAF to the inner surface of the cell membrane, placing it in a position to be activated itself.

After being recruited by RAS, BRAF’s job is to pass the signal to the next protein in the chain, a kinase named MEK. BRAF activates MEK by phosphorylating it, a process that attaches a phosphate group to the MEK protein. This attachment alters its shape and switches it on.

Now active, MEK relays the signal by phosphorylating and activating another protein called ERK. Activated ERK is the final messenger in this cascade and travels from the cytoplasm into the nucleus. Inside the nucleus, ERK activates transcription factors that regulate gene expression, ensuring the cell carries out normal functions like controlled division.

This entire sequence is tightly controlled by feedback mechanisms. Once ERK is activated, it can send signals back up the chain to suppress the pathway. This regulation ensures the growth command is temporary and prevents signaling from becoming excessive.

BRAF Mutations and Uncontrolled Cell Growth

The function of the BRAF/MEK pathway can be disrupted by genetic mutations. A change in the BRAF gene, which provides instructions for the BRAF protein, can alter its structure. The most documented change is the BRAF V600E mutation, where a single error causes the amino acid valine (V) to be replaced by glutamic acid (E) at position 600 of the protein chain.

This substitution has significant consequences, as the change mimics the effect of phosphorylation, the natural “on” switch for the BRAF protein. As a result, the mutated BRAF protein becomes stuck in a permanently active state. It continuously signals downstream to MEK and ERK without needing a prompt from an external growth factor.

This constant, unregulated signaling hijacks the cell’s growth machinery. The pathway, which should only be active for short periods, is now perpetually “on.” It instructs the cell to grow and divide, overriding the normal checkpoints and feedback loops that would otherwise halt proliferation.

BRAF mutations are frequent in certain cancers, such as melanoma, where they are found in approximately half of all cases. These mutations are also common in thyroid cancer, colorectal cancer, hairy cell leukemia, and some non-small cell lung cancers. The presence of a BRAF mutation can be identified through genetic testing of a tumor sample.

Targeting the Pathway with Inhibitors

The discovery that a specific genetic flaw drives certain cancers led to the development of targeted therapies. Unlike traditional chemotherapy, which affects all rapidly dividing cells, these medicines are engineered to interact with specific molecular targets. For cancers driven by BRAF mutations, scientists designed BRAF inhibitors that precisely block the activity of the mutated BRAF protein.

A BRAF inhibitor molecule is shaped to fit into a key site of the BRAF kinase that enables its signaling function. By occupying this site, the inhibitor prevents the mutated BRAF protein from passing the growth signal to MEK. This action shuts off the rogue signal at its source, slowing the uncontrolled proliferation of cancer cells.

While BRAF inhibitors can be effective, cancer cells can develop resistance. For this reason, a MEK inhibitor is often used in conjunction with a BRAF inhibitor. MEK inhibitors work by blocking the next step in the signaling chain, preventing the MEK protein from activating ERK.

Using both a BRAF and a MEK inhibitor provides a more thorough shutdown of the pathway. Studies show this combination therapy leads to higher response rates and can delay drug resistance. This dual blockade makes it more difficult for the cancer cell to reactivate the pathway and continue its growth.

Therapeutic Approaches and Treatment Resistance

Despite the success of combination therapy, many cancers eventually find ways to overcome these drugs through acquired resistance. Cancer cells can evolve new mechanisms to survive by reactivating the growth pathway. For example, a new mutation might arise in the MEK protein that prevents the inhibitor from binding to it.

In other cases, cancer cells can develop resistance by amplifying the BRAF gene, making so many copies of the mutated protein that the inhibitor drugs are overwhelmed. Cells can also find detours around the blockade entirely by activating alternative signaling routes, such as the PI3K-Akt pathway. This means the cancer cell opens a different highway to fuel its growth, rendering the initial therapy less effective over time.