Braf

B-Raf, encoded by the BRAF gene, is a serine/threonine-protein kinase in the RAF family that lies in the middle of the MAPK/ERK signaling pathway. It acts downstream of RAS to activate MEK and, in turn, ERK, transmitting signals that regulate cell growth, differentiation, and survival. The protein contains an N-terminal regulatory region and a C-terminal kinase domain; many oncogenic alterations affect the kinase domain and increase signaling output.

Mutations in BRAF can be activating and contribute to uncontrolled cell proliferation. The most common alteration is V600E, which substitutes valine with glutamic acid at position 600 and is frequent in melanoma and found in other cancers such as thyroid and colorectal cancers. Not all BRAF mutations have identical effects on kinase activity or pathway dynamics; some non-V600 alterations may have distinct functional consequences.

Therapeutically, tumors harboring activating BRAF mutations can be treated with BRAF inhibitors, such as vemurafenib, dabrafenib, or encorafenib. These drugs block B-Raf signaling and reduce tumor growth. Combination therapy with MEK inhibitors (e.g., trametinib, cobimetinib, or binimetinib) is commonly used to enhance efficacy and delay resistance, while also reducing paradoxical activation seen in BRAF wild-type tissues. In BRAF wild-type tumors, BRAF inhibitors can paradoxically activate the pathway and, in some cases, promote secondary skin tumors.

Diagnosis typically involves molecular testing of tumor samples or circulating tumor DNA to identify activating BRAF mutations, guiding the use of targeted therapies. Resistance to BRAF inhibitors remains a clinical challenge, often arising from alternative signaling mechanisms or intratumoral heterogeneity.