Expanding Targets in NSCLC - Episode 1


Transcript: Bruce E. Johnson, MD: Between 10 and 15 years ago, we began to systematically characterize the genetic changes in lung cancers. We described that 1 of the genes that was activated in melanoma was also present in lung cancer. BRAF is mutated in about 2% to 4% of non—small cell lung cancers, and about half of those have the BRAF V600E mutation. The reason why the BRAF V600E mutation is pretty important is because it’s present in the majority of melanomas, and they have developed drugs that are specific for the BRAF V600E mutation as potential therapeutics that could be targeted for that specific mutation.

The mutation within V600E ends up activating the RAF family of kinases, and downstream from them are the MEK kinases. By activating through the mutation of the BRAF gene, you also get activation of MEK. And then it signals through the MAP kinase pathway and ends up driving cell proliferation.

We discovered in melanoma and lung cancer that if you administer BRAF inhibitors, you end up getting a subsequent paradoxical increase in the MAP kinase signaling pathway. This ends up leading to a reactivation of the tumor, and also the development of skin cancers. This was observed when both patients with melanoma as well as lung cancers were treated, they would commonly develop skin cancers that would end up having to be taken off, or surgically removed.

The other thing that was fortuitous is that there were effective drugs that were developed against MEK that could then be combined with the BRAF inhibitors.

When one treats patients with a BRAF inhibitor, you are able to suppress the signaling pathway. The common mechanism of resistance is activation of the downstream MEK kinase pathway. So when that gets upregulated, it has the untoward effects of allowing the cancer to regrow, and also to develop skin cancer. Therefore, if you could combine both the BRAF inhibition and the MEK inhibition, you can delay the development of resistance because you block the activation of the MEK kinase pathway and prevent the adverse effect of developing skin cancers that are related to the activation of the MEK kinase and the downstream MAP kinase pathways.

Transcript Edited for Clarity