Because BRAF activating mutations have been found in so many different types of cancer, there has been a concerted push to develop BRAF-specific therapies that are both safe and effective. As a result of these efforts, 3 BRAF inhibitors and 5 combinations comprising a BRAF inhibitor with an additional agent or agents have been developed and approved for use in the treatment of various cancers, including melanoma, non-small cell lung cancer, anaplastic thyroid cancer, and colorectal cancer.
To date, only individuals whose tumors carry the BRAFV600 mutation have had any benefit from any of the available regimens, and that advantage is generally temporary. Treatments for BRAF mutations other than V600 have been less effective, and combination therapy is probably necessary to overcome resistance mechanisms, but multi-drug regimens are often excessively toxic, all of which preclude appropriate management of BRAF-mutant malignancies.
Newer RAF inhibitors may be more successful and maybe safer, and more sensible combination therapies are being explored in the clinic, all thanks to a better knowledge of how BRAF mutations signal through the RAS/MAPK pathway. In this article, researchers outlined the RAS/MAPK pathway’s role under RAF signaling, offered data on single-agent and combination RAF targeting efforts, discussed new combinations, summarized the toxicity of the various drugs in clinical development, and predicted the future of the area.