Targeting the multifaceted BRAF in cancer: New directions.

Activating mutations in the mitogen-activated protein kinase (MAPK) pathway represent driver alterations governing tumorigenesis, metastasis, and therapy resistance. MAPK activation predominantly occurs through genomic alterations in and . BRAF is an effector kinase that functions downstream of and propagates this oncogenic activity through MEK and ERK. Across cancers, alterations include gain-of-function mutations, copy-number alterations, and structural rearrangements. In cancer patients, BRAF-targeting precision therapeutics are effective against Class I alterations (p.V600 hotspot mutations) in tumors such as melanomas, thyroid cancers, and colorectal cancers. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in some cancers. Here we discuss the diverse forms of alterations found in human cancers and the strategies to inhibit them in patients harboring cancers of distinct origins.