title: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling.
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.
authors: Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Zoi
authors: Z
authors: Karoulia
authors: Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Yang
authors: Y
authors: Wu
authors: Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Tamer A
authors: TA
authors: Ahmed
authors: Department of Biochemistry, Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Qisheng
authors: Q
authors: Xin
authors: Department of Oncological Sciences, Liver Cancer program, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Julien
authors: J
authors: Bollard
authors: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19014, USA.
authors: Clemens
authors: C
authors: Krepler
authors: Department of Oncological Sciences, Department of Dermatology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Xuewei
authors: X
authors: Wu
authors: Plexxikon Inc., Berkeley, CA 94710, USA.
authors: Chao
authors: C
authors: Zhang
authors: Plexxikon Inc., Berkeley, CA 94710, USA.
authors: Gideon
authors: G
authors: Bollag
authors: Molecular and Cellular Oncogenesis Program, Tumor Microenvironment and Metastasis Program, and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19014, USA.
authors: Meenhard
authors: M
authors: Herlyn
authors: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: James A
authors: JA
authors: Fagin
authors: Department of Oncological Sciences, Liver Cancer program, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Amaia
authors: A
authors: Lujambio
authors: 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: evripidis.gavathiotis@einstein.yu.edu.
authors: Evripidis
authors: E
authors: Gavathiotis
authors: 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: poulikos.poulikakos@mssm.edu.
authors: Poulikos I
authors: PI
authors: Poulikakos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf