TY - JOUR
T1 - An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling
AU - Karoulia, Zoi
AU - Wu, Yang
AU - Ahmed, Tamer A.
AU - Xin, Qisheng
AU - Bollard, Julien
AU - Krepler, Clemens
AU - Wu, Xuewei
AU - Zhang, Chao
AU - Bollag, Gideon
AU - Herlyn, Meenhard
AU - Fagin, James A.
AU - Lujambio, Amaia
AU - Gavathiotis, Evripidis
AU - Poulikakos, Poulikos I.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/9/12
Y1 - 2016/9/12
N2 - 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 BRAFV600E cancers, in which first-generation RAF inhibitors have been ineffective.
AB - 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 BRAFV600E cancers, in which first-generation RAF inhibitors have been ineffective.
UR - http://www.scopus.com/inward/record.url?scp=84981725596&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2016.06.024
DO - 10.1016/j.ccell.2016.06.024
M3 - Article
C2 - 27523909
AN - SCOPUS:84981725596
SN - 1535-6108
VL - 30
SP - 485
EP - 498
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -