Therapeutic strategies for different classes of BRAF and MEK mutations. Therapeutic strategies for different classes of BRAF and MEK mutations. The efficacy of specific inhibitors (green “+,” active; red “−,” inactive) and a potential rational therapeutic approach (blue boxes) are shown for each class of BRAF or MEK mutation. In general, the therapeutic approach for each class of mutation is based on its classification as an “activator” or “amplifier,” with activators requiring targeting downstream of or at the level of the mutation, and with amplifiers requiring upstream inhibition in combination with downstream inhibition. The level at which the pathway is targeted in each scenario is marked in orange. For MEK mutants, upstream inhibition would include RAF inhibition in BRAFV600 cancers or RTK inhibition in RAS/BRAF–wild-type cancers. In some cases, upstream inhibition may be helpful even when targeting activator mutations as a means of disrupting adaptive feedback reactivation of MAPK signaling, for example, as when adding an RTK inhibitor (e.g., anti-EGFR antibodies) in BRAFV600 colorectal cancers (CRC). Rona Yaeger, and Ryan B. Corcoran Cancer Discov 2019;9:329-341 ©2019 by American Association for Cancer Research