An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

• DOI: 10.1016/j.ccell.2016.06.024
• Publication Date: 2016-08-12T07:29:32Z
• Authors: Zoi Karoulia; Yang Wu; Tamer A. Ahmed; Qisheng Xin; Julien Bollard; Clemens Krepler; Xuewei Wu; Chao Zhang; Gideon Bollag; Meenhard Herlyn; James A. Fagin; Amaia Lujambio; Evripidis Gavathi...; Poulikos I. Pouli...
• Keywords: Proto-Oncogene Proteins B-raf; Mice; HEK293 Cells; Cell Line, Tumor; Animals; Humans; Protein Kinase Inhibitors; Signal Transduction; 3. Good health

The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF(V600E) cancers, in which first-generation RAF inhibitors have been ineffective.