Malignant Melanoma: Contemporary Management - Episode 17

The Role of BRAF Mutations in Melanoma


My name is Adil Daud. I’m a medical oncologist. I work at the University of California, San Francisco, where I direct melanoma research and the melanoma program.

The role of BRAF mutations in melanoma is an interesting 1, and it’s a switch that’s present in melanoma cells. And if you think about the cell machinery, there are a lot of on-off switches in the cell. And BRAF is 1 of those switches that can be in an on position or an off position. When you have a BRAF mutation like the V600E or V600K mutation, that’s like having a switch jammed in the on position. And normally the cell is able to turn off when there’s a lack of external signals; it’s able to turn on when there are more external signals, but once you have that mutation, the cell is not able to turn off. And so it keeps on dividing and keeps on growing. That’s the significance of the BRAF mutation.

It has a long history, melanoma. When it was first found, what was interesting was that a lot of benign moles—you know, I have a whole bunch of them—a lot of moles also have BRAF mutations. And so people were kind of surprised that something that is present at such an early stage of melanoma development—you know, right at that stage where you have benign moles—seems to be so important in late-stage or advanced-stage melanoma. In cell lines, if you use a BRAF inhibitor, it definitely causes significant shrinkage in tumors in mice and in culture. And when patients were tested with BRAF inhibitors, which was back in 2008 and 2009, patients were noticed to have dramatic response. Like marked responses—like within a month or 2, tumors were half in size.

However, resistance developed quickly, and 1 of the observations that people had from cell culture in animal models is that if you added a second kind of inhibitor, a MEK inhibitor, which is the downstream kinase to BRAF, that causes vertical inhibition, you could think of it as having a river that’s flowing: you block it with a dam, and ultimately it’s going to top that dam. If you have a second dam, you are going to hold whatever goes over the first dam more. That’s the theory behind the vertical inhibition at 2 different places at BRAF and MEK, so that combination basically has proven to be a supereffective strategy in dealing with the BRAF-mutant melanomas.

The biggest limitation is the development of resistance. A lot of times in cancer therapy, if you block a single enzyme like BRAF, you’re essentially selecting for variants, cell variants, that don’t need BRAF as much—don’t have such an immediate requirement for BRAF. And that’s turned out to be the case in melanoma, that we haven’t identified mutations in BRAF per se, but we’ve identified a lot of different conditions where the cells don’t seem to need BRAF as much in terms of continuing to grow and spread. And that’s been the case in melanoma, that a lot of the resistance to BRAF inhibitors develops relatively rapidly and is attributable to phenotypic resistance rather than genotypic resistance. You know, we haven’t been able to find secondary mutations in BRAF that make the BRAF inhibitors less likely to bind to BRAF and inhibit it. But it’s more that the cell just seems to reorganize its growth, so it doesn’t need BRAF, so that’s not as critical an enzyme, and somehow that cell is able to grow and divide without that pathway. And that seems to be—I’m just summarizing many years of research into BRAF inhibition and resistance.

Transcript Edited for Clarity