What should I know about the BRAF, NRAS and KRAS gene mutations?

Throughout this course, we've explored the impact of chromosomal mutations on multiple myeloma, but they're only part of the story. Gene mutations can also play a crucial role in the disease. In this HealthTree University lesson, we'll shift our focus to specific gene mutations that can be detected in myeloma, how they influence disease progression and what they mean for treatment strategies.

What should I know about gene mutations that can occur in multiple myeloma? So a lot of what we've talked about has been, you know, whole chromosome or changes in expression. But there are some mutations, which don't change the expression of the gene, but they change how it functions. And the most famous ones would be KRAS, NRAS, BRAF and, some patients, in fact, with FGFR3. They'll get, a single nucleotide, a single amino acid gets changed in that protein and it activates it so that, that the, the gene is like constantly on, constantly signaling and it's constantly signaling growth. And so it's like putting your foot on the accelerator and it's telling, it's getting a signal to the cell that it should divide.

A lot of other cancers. We can there are targeted therapies which inhibit, these activated, proteins called kinase inhibitors. And, so far there, there don't seem to be any good. I want you particularly well with multiple myeloma, but it has been. I hope that we would find some targeted therapy that would, the active against the these mutations.

Individual genes may have just a single code change, a mutation that is, a single change in a gene that can now cause that gene to function differently. Now you'll notice that in this slide I'm showing how common some of these are. And look at the top of the list is what's called KRAS and NRAS through research and understanding then testing what these genes do. We now understand that the RAS genes signal cells to divide and proliferate. And it's a normal gene in the normal genome. But in myeloma oftentimes that gene is mutated and it's mutated. So that that gene functions at a higher level. Functioning at a higher level means it's signaling in that cell to divide and proliferate at a higher level. That's what tumor cells do. That's what we don't want them to do.

So there are a couple useful pieces of information here. One is we start understanding which genes contribute to the myeloma trait of its proliferation, or maybe its migration to the marrow. But it also gives us another useful piece of information. If I can block that KRAS gene and stop it from overreacting, I might have an effective therapy. So, in fact, a lot of research at academic institutes and at pharma companies are trying to develop drugs that will specifically target the genes that are mutated in myeloma so that the drug will stop that gene from functioning. And so there's a lot of research being done. And you'll see a gene there called BRAF. There's actually a good therapy, drug for the treatment of tumors that have BRAF mutations.

So this is also giving us information based on the genetic mutations as to how aggressive the disease might be and what there, what effective therapeutics there might be or what targets we should be testing to try to treat this disease.

How would someone know if they have a BRAF, RAS, KRAS, or NRAS mutation? Only way that that you could find out if you've got a point mutation in, almost any, any gene in multiple myeloma, like KRAS or NRAS or BRAF for p53, would be if you had, sequencing done typically would be next generation sequencing. And you would, would want to include a variety of genes because, you know, most of the only a few genes are commonly mutated. So NRAS, BRAS, they would be about 20% each. But then the other genes are, you know, 10% or less. And so you really need to sequence a lot of genes in order to identify which ones might be a good individual.

If you have one of these mutations, could you use a therapy from another cancer that's directed at that mutation? Well, certainly there's, a push to do targeted therapy in multiple myeloma. And what that means is to take drugs which are active, maybe other cancers, against a given mutation and apply them to multiple myeloma patients that share the same mutation. Those studies are very difficult to do because any given mutation tends to be quite uncommon. But they are being done in one study that is going on. There's a study from the National Cancer Institute called Tapur. And these are very large studies which brought together a number of different drugs in the patients, has their tumor sequenced. And then, the drug which matches that patient's mutation is used in a clinical trial.

But I would say up to date the, the, that was that approach, has shown, a lot of hurdles, a lot of recovery in getting it done. And it hasn't had a lot of successes, in multiple myeloma. And so I think we we need to, you know, we need to do more studies before we can see. That's really for fine tuning.

Why don't myeloma patients respond well to BRAF inhibitors? Is the BRAF mutation in myeloma different from that in breast or lung cancer, or is another factor at play? Probably, there's some data from a few case studies where, the patient has a transient response. And, but the issue is that the patient has got a BRAF mutation, typically that's in a subclone. And there's another subclone, it doesn't have a BRAF mutation. And so when you treat it with the inhibitor you just allow the other some form to grow.

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