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

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 Gavathiotis, Poulikos I. Poulikakos

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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. Karoulia et al. show that the biochemical effect of RAF inhibitors in cells is the combined outcome of two distinct allosteric mechanisms. These results provide a blueprint for the development of improved RAF inhibitor-based therapeutic strategies for BRAF-dependent tumors.

Original languageEnglish (US)
JournalCancer Cell
DOIs
StateAccepted/In press - Sep 1 2015

Fingerprint

Dimerization
Drug Resistance
Guanosine Triphosphate
Thyroid Neoplasms
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Karoulia, Z., Wu, Y., Ahmed, T. A., Xin, Q., Bollard, J., Krepler, C., ... Poulikakos, P. I. (Accepted/In press). An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. Cancer Cell. https://doi.org/10.1016/j.ccell.2016.06.024

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. / Karoulia, Zoi; Wu, Yang; Ahmed, Tamer A.; Xin, Qisheng; Bollard, Julien; Krepler, Clemens; Wu, Xuewei; Zhang, Chao; Bollag, Gideon; Herlyn, Meenhard; Fagin, James A.; Lujambio, Amaia; Gavathiotis, Evripidis; Poulikakos, Poulikos I.

In: Cancer Cell, 01.09.2015.

Research output: Contribution to journalArticle

Karoulia, Z, Wu, Y, Ahmed, TA, Xin, Q, Bollard, J, Krepler, C, Wu, X, Zhang, C, Bollag, G, Herlyn, M, Fagin, JA, Lujambio, A, Gavathiotis, E & Poulikakos, PI 2015, 'An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling', Cancer Cell. https://doi.org/10.1016/j.ccell.2016.06.024
Karoulia, Zoi ; Wu, Yang ; Ahmed, Tamer A. ; Xin, Qisheng ; Bollard, Julien ; Krepler, Clemens ; Wu, Xuewei ; Zhang, Chao ; Bollag, Gideon ; Herlyn, Meenhard ; Fagin, James A. ; Lujambio, Amaia ; Gavathiotis, Evripidis ; Poulikakos, Poulikos I. / An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. In: Cancer Cell. 2015.
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