Insights From: Geoffrey Thomas Gibney, MD, MedStar Georgetown University Hospital
Geoffrey Thomas Gibney, MD: We know that melanoma has 1 of the highest gene-mutation rates for all the tumor types, and this has very significant implications in both immunotherapy as well as targeted therapy. Many of these mutations are driver mutations that cause the cells to proliferate at faster rates, cause them to migrate, and can also bring in vascular supply so that they’re well-nourished and actually can grow and divide at faster rates. Some of these mutations are very well defined and are seen fairly often within melanoma tumors. The ones that we most often see are NRAS, c-KIT, and BRAF. The first identified mutation, a driver mutation, was actually NRAS in melanoma. Clinical development has been very difficult in finding a very effective targeted strategy. Whereas, there’s been better development with c-KIT as well as in BRAF-targeted therapy approaches.
In particular, the BRAF mutation happens in about 50% of patients’ tumors, especially if it’s been sun exposed and is arising from the skin. That mutation leaves the protein kinase in a constitutively active state, so it is continuously driving signaling through the MAP kinase pathway that leads to an aggressive phenotype within the melanoma cell. We know that it doesn’t actually cause a melanocyte to become melanoma, but when it’s introduced into the tumor cell it causes it to be much more aggressive and faster growing, and it is able to migrate and resist cell death. The targeted therapy approaches have been very effective because the cells are very addicted to this pathway. So with the selective inhibitors, blocking that pathway has shut down the cell proliferation. And in animal experiments, as well as in patients, we see a very dramatic shrinkage in tumors.
The BRAF mutation is actually an oncodriver—not enough to turn a melanocyte into melanoma, but it makes it more aggressive. So it drives a pathway when it’s mutated. The most common mutation is the BRAF V600 position, and that leaves it constitutively on. That protein kinase then drives signaling through the MAP [mitogen-activated pathway] kinase, and that can lead to a number of processes within the tumor cell that allow it to grow faster, to proliferate, to avoid apoptosis, to bring in vasculature, and to migrate. So it makes it a much more aggressive phenotype.
So the BRAF target is a very specific mutation within a pathway, and it turns on that pathway in a very uniform, predictable pattern for the most part. So if you were able to block it, it can actually be very effective in shutting down the activity of the cancer cell. So we now have been able to develop very selective BRAF inhibitors that inhibit just the mutant protein kinase, the BRAF, with very little off-target effect, which makes it a very selective targeted therapy that can be blocked within a tumor cell. The tumor cell, when it is blocked—those that harbor the BRAF mutation actually shut down cell proliferations, and tumors in experimental models as well as in people can be seen to shrink very dramatically.