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 - Funding Information:
We are grateful to T. Merghoub, D. Solit, and A. Ribas for providing melanoma cell lines, B. Qeriqi and E. de Stanchina for help with animal studies, and N. Rosen for reagents and useful discussions. We thank S.A. Aaronson, A.K. Aggarwal, S. Chandarlapaty, Z.Q. Pan, J.R. Peterson, and A. Samatar for critical reading of the manuscript. E.G. acknowledges the support by NIH grant (1R01CA178394), the Sidney Kimmel Foundation for Cancer Research, the Gabrielle's Angels Foundation for Cancer Research, and the Alexandrine and Alexander L. Sinsheimer Foundation. P.I.P. would like to acknowledge the Sidney Kimmel Foundation for Cancer Research, the Melanoma Research Foundation, the Dermatology Foundation, the Melanoma Research Alliance, the Harry J. Lloyd Charitable Trust, a TCI Developmental Award, and the TCI Young Scientist Cancer Research Award for funding. A.L. acknowledges the AASLD Pinnacle Research Award for funding. J.B. thanks the Claude Rose Award from the CECED. C.Z. and G.B. are employees of Plexxikon Inc.
Funding Information:
We are grateful to T. Merghoub, D. Solit, and A. Ribas for providing melanoma cell lines, B. Qeriqi and E. de Stanchina for help with animal studies, and N. Rosen for reagents and useful discussions. We thank S.A. Aaronson, A.K. Aggarwal, S. Chandarlapaty, Z.Q. Pan, J.R. Peterson, and A. Samatar for critical reading of the manuscript. E.G. acknowledges the support by NIH grant ( 1R01CA178394 ), the Sidney Kimmel Foundation for Cancer Research , the Gabrielle's Angels Foundation for Cancer Research , and the Alexandrine and Alexander L. Sinsheimer Foundation . P.I.P. would like to acknowledge the Sidney Kimmel Foundation for Cancer Research, the Melanoma Research Foundation, the Dermatology Foundation, the Melanoma Research Alliance, the Harry J. Lloyd Charitable Trust, a TCI Developmental Award, and the TCI Young Scientist Cancer Research Award for funding. A.L. acknowledges the AASLD Pinnacle Research Award for funding. J.B. thanks the Claude Rose Award from the CECED. C.Z. and G.B. are employees of Plexxikon Inc.
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.
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UR - http://www.scopus.com/inward/citedby.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 -
