Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK

Cancer Cell. 2012 Aug 14;22(2):222-34. doi: 10.1016/j.ccr.2012.06.014.

Abstract

Here, we have investigated the role of the Notch pathway in the generation and maintenance of Kras(G12V)-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and RBPJ are essential for the formation of NSCLCs. Of importance, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and reduced phosphorylated ERK without changes in phosphorylated MEK. Mechanistically, we show that HES1 directly binds to and represses the promoter of DUSP1, encoding a dual phosphatase that is active against phospho-ERK. Accordingly, GSI treatment upregulates DUSP1 and decreases phospho-ERK. These data provide proof of the in vivo therapeutic potential of GSIs in primary NSCLCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Dual Specificity Phosphatase 1 / metabolism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology
  • Mice
  • Mutant Proteins / metabolism
  • Phosphorylation / drug effects
  • Presenilin-1 / metabolism
  • Presenilin-2 / metabolism
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Receptors, Notch / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Transcription Factor HES-1
  • Treatment Outcome
  • ras Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Enzyme Inhibitors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Mutant Proteins
  • Presenilin-1
  • Presenilin-2
  • Psen2 protein, mouse
  • Receptors, Notch
  • Repressor Proteins
  • Transcription Factor HES-1
  • HES1 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • Amyloid Precursor Protein Secretases
  • ras Proteins

Associated data

  • GEO/GSE38054