RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.