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

Cancer Cell. 2016 Sep 12;30(3):485-498. doi: 10.1016/j.ccell.2016.06.024.

Zoi Karoulia ¹, Yang Wu ², Tamer A Ahmed ¹, Qisheng Xin ², Julien Bollard ³, Clemens Krepler ⁴, Xuewei Wu ¹, Chao Zhang ⁵, Gideon Bollag ⁵, Meenhard Herlyn ⁴, James A Fagin ⁶, Amaia Lujambio ³, Evripidis Gavathiotis ⁷, Poulikos I Poulikakos ⁸

Affiliations

1 Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2 Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3 Department of Oncological Sciences, Liver Cancer program, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4 Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19014, USA.
5 Plexxikon Inc., Berkeley, CA 94710, USA.
6 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7 Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: [email protected].
8 Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: [email protected].

PMID: 27523909 DOI: 10.1016/j.ccell.2016.06.024

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 BRAF(V600E) cancers, in which first-generation Raf inhibitors have been ineffective.

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