Yin and yang represent complementary (rather than opposing) forces that interact to form a dynamic system in which the whole is greater than the assembled parts as in the BRAF-MEK complex. In healthy signaling pathways, a dynamic flow balances and rebalances these energies as observed when MEK becomes phosphorylated and disassociates transiently from BRAF. Disruption of this balance by oncogenic mutations in BRAF leads to constitutive dissociation of the complex and an unhealthy activation of the pathway.
Cover illustration designed by Allison Bruce.
The MAPK signaling pathway is one of the first pathways discovered to be important for cancer. The pathway works by sending signals received from outside the cell through a series of proteins to activate genes that cause cells to grow and divide.
Some of the key players in this pathway found inside the cell include RAS and RAF, which then activate MEK and ERK proteins. You can learn more about this pathway here.
Not All Inhibitors Are Created Equal
The RAS and RAF proteins come in different “flavors” (scientifically known as isoforms). One isoform of the RAS protein is called KRAS and one isoform of the RAF protein is called BRAF. Mutations in KRAS and BRAF proteins are associated with different cancers. One potential strategy for these cancers is to block the MEK protein since mutations in KRAS or BRAF both work through the MEK.
We’ve known that different MEK inhibitors may be more or less effective depending on the KRAS or BRAF preclinical model. Scientists at Genentech have made an important step to figure out why this is the case.
A “Complex” Relationship
We’ve learned that some MEK inhibitors work better in BRAF-mutant models because they bind tightly to and interfere with the action of the MEK protein. However in KRAS-mutant tumors, other MEK inhibitors work by causing the RAF protein to stick to the MEK protein forming what’s scientists call a “complex” of protein.
These are important insights into how different MEK inhibitors may work, but it also has implications for BRAF inhibitors.
Like MEK inhibitors, BRAF inhibitors also come in different varieties, and it is possible that they too may work in different ways. Turning their attention to BRAF, the same team of scientists at Genentech confirmed that this is indeed the case.
First, they showed that BRAF and MEK are often “stuck together” inside of cancer cells and form a complex. This is important, because they also found that “trapping” or stabilizing this complex can interfere with the RAS-RAF pathway.
Interestingly, the team discovered that some BRAF inhibitors may stabilize this complex, but others can actually destabilize it. Similar to what they found for MEK inhibitors, they found that BRAF inhibitors can have different effects based on the way they can bind to and interact with other proteins.
Studies on MEK and BRAF inhibitors teach us important lessons for developing investigational small molecule medicines for cancer.
- 1. We now know that kinase inhibitors can affect both proteins themselves individually, but also how proteins interact with each other.
- 2. When developing new medicines now, we need to consider that proteins do not exist in isolation but often together with other proteins.
Read more about these important findings in the Cancer Cell paper, “Structure of the BRAF:MEK complex reveals a kinase activity independent role for BRAF in MAPK Signaling.”