V600E

V600E refers to a specific point mutation in the BRAF gene, in which valine (V) at amino acid position 600 is replaced by glutamic acid (E). This substitution creates a constitutively active BRAF kinase, leading to continuous stimulation of the MAPK signaling pathway and increased cell proliferation. V600E is one of the most common activating BRAF mutations observed in human cancers.

The BRAF gene encodes a serine/threonine kinase that sits in the RAS-RAF-MEK-ERK signaling cascade. The V600E mutation stabilizes BRAF in an active conformation, driving downstream signaling independent of upstream RAS activity. This promotes cell growth and survival and can contribute to oncogenesis in tumors carrying the mutation.

Clinical relevance includes diagnostic and therapeutic implications. V600E is frequent in melanoma and papillary thyroid carcinoma and occurs in subsets of colorectal and lung cancers, among others. Detection is commonly performed by DNA sequencing or PCR-based assays, and immunohistochemistry using mutation-specific antibodies (such as VE1) can serve as a surrogate test in some settings.

Therapeutically, tumors with BRAF V600E may respond to targeted inhibitors of BRAF (for example, vemurafenib or dabrafenib) and often benefit from combination therapy with MEK inhibitors (such as trametinib), which can improve efficacy and delay resistance. Resistance can arise through multiple mechanisms, including reactivation of the MAPK pathway or activation of alternative signaling routes. In colorectal cancer, responses to BRAF inhibitors are typically less durable without combination strategies.

Testing for V600E is routinely used to guide treatment decisions in melanoma and papillary thyroid carcinoma and informs prognosis and management in other cancers.