I sat through some presentations yesterday on melanoma, and one in particular that discussed resistance to BRAF therapy. As you know, after 6 months on a BRAF inhibitor about half of patients will see their tumors start to grow again. A lot of people have tried to understand why this happens, and the MRF funded a researcher who has done good work on this area.
I have also heard that some doctors have started cycling BRAF inhibitors on and off. In other words, give the drug for a while then stop for a while before starting again.
Finally, I heard that a lot of colorectal cancers also have BRAF V600e mutations, but BRAF inhibitors haven't worked in those cancers
A researcher yesterday said that colorectal cancers readily activate a compount called EGFR, a receptor on the cell surface that signals pathways that lead to cell growth. One of those pathways, the MAPK/ERK pathway, includes BRAF. Another is called the AKT pathway.
Inhibiting BRAF shuts down the MAPK/EFK pathway. In colorectal cancer this causes upstream activation of EGFR, which in turn activates the AKT pathway. Imagine having a favorite road you drive to go to work. if there is a wreck on that road you find a different path. You may not like it as well, but it gets you there. The same is true here. The cancer prefers growing by an activated MAPK/ERK pathway, but is perfectly happy using the AKT if it needs to do so.
It turns out that melanoma cells really don't like to activiate EGFR. Unlike colorectal cancer cells, which activate it easily and flourish under that system, melanoma has a hard time with this. (Imagine that your alternate path to work is a dirt road through the mountains instead of the 4 lane highway you normally use.) With enough BRAF inhibition the activation can and does occur, but the cells that grow with this mechanism are weak and don't do well. Removing the BRAF inhibition allows the stronger cells to come back and wipe out the EGFR activated cells. Then re-inducing BRAF inhibition wipes out the other cells.
Bottom line is that cycling BRAF inhibitors on and off may provide longer lasting benefit. Hopefully this will be studied further and, if it is validated, become a new approach to treating BRAF mutant melanomas.