BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-indep...

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Published in:Cancer cell Vol. 28; no. 3; p. 370
Main Authors: Yao, Zhan, Torres, Neilawattie M, Tao, Anthony, Gao, Yijun, Luo, Lusong, Li, Qi, de Stanchina, Elisa, Abdel-Wahab, Omar, Solit, David B, Poulikakos, Poulikos I, Rosen, Neal
Format: Journal Article
Language:English
Published: United States 14.09.2015
Subjects:
Cell Line, Tumor
Dimerization
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Humans
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - genetics
Mutation - genetics
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - genetics
ras Proteins - genetics
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary:ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.
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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2015.08.001