What Is Raf Kinase and How Does It Cause Cancer?

Raf kinase is an enzyme that acts as a communication relay within the body’s cells. By relaying messages from the cell’s surface to its nucleus, Raf kinase helps manage fundamental processes like cellular growth, division, and survival.

The Role of Raf Kinase in Cell Signaling

Raf kinase is a participant in a signaling cascade known as the MAPK/ERK pathway. This system acts like a chain of command, translating signals from outside the cell into specific instructions. The process begins when external molecules, like growth factors, bind to receptors on the cell’s outer membrane, triggering a series of protein activations.

The signal is first passed to a protein called Ras, which recruits and engages Raf kinase. Raf continues the cascade by activating the next protein, MEK, through phosphorylation. MEK then activates the final protein, ERK, which travels to the cell nucleus to regulate genes that control cell proliferation and survival. When this pathway operates correctly, it ensures cells divide only when necessary, maintaining tissue health.

Types of Raf Kinases

The Raf kinase family has three distinct proteins, or isoforms: A-RAF, B-RAF, and C-RAF. While structurally similar, these isoforms have different patterns of activity and expression. C-RAF is found in nearly all tissues, A-RAF is most prominent in the urogenital system, and B-RAF is primarily expressed in neural and hematopoietic tissues.

All three isoforms can activate the MEK protein, but B-RAF is the most potent activator. This higher baseline activity helps explain why B-RAF is the most frequently mutated Raf isoform in human diseases, making it a primary focus of research.

Raf Kinase Mutations and Cancer Development

Cancer can develop when the genes that provide instructions for proteins like Raf kinase are altered. For Raf kinase, this often involves the BRAF gene, where a point mutation known as V600E is common in several cancers. This single error swaps one amino acid for another in the protein’s structure, leading to a permanently altered protein.

The V600E mutation jams the B-RAF protein in the “on” position, like a car’s accelerator pedal being stuck. This causes the MAPK/ERK pathway to become constantly active, telling the cell to grow and divide without external signals, which is a hallmark of cancer. BRAF mutations are a driving force in approximately 50% of melanomas, 40% of papillary thyroid cancers, and 10% of colorectal cancers.

Therapeutic Targeting of Raf Kinase

The role of BRAF mutations in cancer led to the development of targeted therapies. Unlike traditional chemotherapy, these drugs attack specific molecular features of cancer cells. B-RAF inhibitors, like vemurafenib and dabrafenib, are molecules engineered to fit into the mutated B-RAF protein, blocking its activity and halting uncontrolled cell growth.

However, cancer cells can develop resistance to a single inhibitor by reactivating the pathway through other means, such as by increasing MEK activity. To counteract this, a strategy combines B-RAF inhibitors with MEK inhibitors. This combination therapy attacks the pathway at two points, making it harder for the cancer to find an escape route and delaying the development of resistance.