RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

“ATP competitive inhibitors of the BRAFV600E oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAFWT). In this study, we investigate the biochemical mechanism of wild-type RAF (RAFWT) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAFV600E and RAFWT enzymes. We show that activation of RAFWT is ATP dependent and directly linked to RAF kinase activity…”