BRAF and MEK in Melanoma

Source: OncLive, October 2019

Hussein A. Tawbi, MD, PhD: In terms of the role of the BRAF mutation in melanoma, up to half the patients with melanoma have a BRAF mutation in their tumor. And in those patients, the BRAF mutation actually is oncogenic, which means it actually drives the development of the cancer. We understand very well the pathway that’s involved in that. It’s called the MAP kinase pathway. Because of the mutation, we have a variant signaling for that pathway that drives the cell into continuous proliferation and growth. We also know it affects the tumor microenvironment to make it less immunogenic and less responsive to immune therapy. And so those mutations, again, appear in about half the patients. Specifically, about 80% to 85% of those mutations are V600E. Another 5% to 7% are V600K. Then there’s a smaller percentage of other mutations that could be relevant.

The presence of a BRAF mutation, from my perspective, simply gives us additional alternatives for those patients in terms of using targeted therapy. In the past, there used to be questions about the prognostic significance of having a BRAF mutation, or it seemed to be a bit more of an aggressive disease. But I think the landscape has changed. Now we have therapy that can alter the outcomes of those patients.

The BRAF mutation is a mutation that affects the BRAF gene, which is actually part of the MAP kinase pathway. The MAP kinase pathway is basically a signaling pathway that starts at the cell surface and signals through RAS, then RAF, then MEK, and ERK. ERK is the last protein that actually gets into the nucleus and changes the expression of genes and so on. So that kind of pathway is sequential. When we have a BRAF mutation, the BRAF itself becomes the oncogenic signal, so to speak, and kind of takes over and starts firing through that pathway and activates MEK, activates ERK, and leads to cell proliferation.