BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition Journal Article


Authors: Yao, Z.; Torres, N. M.; Tao, A.; Gao, Y.; Luo, L.; Li, Q.; de Stanchina, E.; Abdel-Wahab, O.; Solit, D. B.; Poulikakos, P. I.; Rosen, N.
Article Title: BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition
Abstract: 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. © 2015 Elsevier Inc.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; protein expression; unclassified drug; gene mutation; nonhuman; mouse; enzyme inhibition; animal experiment; animal model; drug effect; enzyme inhibitor; chemosensitivity; cancer resistance; cancer inhibition; drug mechanism; binding site; dimerization; feedback system; negative feedback; doxycycline; b raf kinase; lapatinib; drug protein binding; monomer; allosterism; dimer; vemurafenib; dabrafenib; trametinib; human; priority journal; article; 3t3 cell line; bgb 659; encorafenib
Journal Title: Cancer Cell
Volume: 28
Issue: 3
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2015-09-14
Start Page: 370
End Page: 383
Language: English
DOI: 10.1016/j.ccell.2015.08.001
PROVIDER: scopus
PUBMED: 26343582
PMCID: PMC4894664
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    359 Rosen
  2. David Solit
    431 Solit
  3. Zhan Yao
    22 Yao
  4. Neilawattie Merna Torres
    14 Torres
  5. Yijun   Gao
    7 Gao
  6. Qi Li
    1 Li