Disruption of CRAF-Mediated MEK activation is required for effective mek inhibition in KRAS mutant tumors Academic Article uri icon

Overview

MeSH Major

  • Drug Resistance, Neoplasm
  • MAP Kinase Kinase 1
  • Melanoma
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • TNF Receptor-Associated Factor 3
  • ras Proteins

abstract

  • MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

publication date

  • May 12, 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4049532

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2014.03.011

PubMed ID

  • 24746704

Additional Document Info

start page

  • 697

end page

  • 710

volume

  • 25

number

  • 5