Figure 1. Paradoxical activation (PA) of the RAS pathway and its potential mechanisms.

(A) Schematic of the RAS/RAF/MEK/ERK signaling pathway and schematic of the PA concept. Whereas a RAF inhibitor can effectively inhibit RAF signaling to MEK in RAF mutant cancers, a RAF inhibitor can increase RAF signaling to MEK in cells without a RAF mutation (RAF wt). Gray triangles indicate directions of increasing RAF inhibitor (x-axis) and increasing RAF activity (y-axis) in the schematic. (B) Mechanisms that have been proposed to contribute to PA include RAF inhibitor-driven RAF dimer potentiation (DP), negative cooperativity (NC) for drug binding in trans within a RAF dimer once one protomer has bound drug, and the regulation of RAF kinase activity through conformational autoinhibition (CA).