Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors

Cancer Cell. 2014 May 12;25(5):697-710. doi: 10.1016/j.ccr.2014.03.011. Epub 2014 Apr 17.

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.

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Cell Line
  • Coumarins / pharmacology
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HEK293 Cells
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / chemistry
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Mice
  • Mice, Nude
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Sulfonamides / pharmacology
  • Surface Plasmon Resonance
  • TNF Receptor-Associated Factor 3 / genetics*
  • TNF Receptor-Associated Factor 3 / metabolism
  • Vemurafenib
  • raf Kinases / metabolism
  • ras Proteins / genetics*

Substances

  • Benzamides
  • Coumarins
  • Indoles
  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyridones
  • Pyrimidinones
  • RNA, Small Interfering
  • RO5126766
  • Sulfonamides
  • TNF Receptor-Associated Factor 3
  • Vemurafenib
  • trametinib
  • mirdametinib
  • Diphenylamine
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Associated data

  • PDB/3WIG