Interferon α/β Enhances the Cytotoxic Response of MEK Inhibition in Melanoma

Mol Cell. 2015 Mar 5;57(5):784-796. doi: 10.1016/j.molcel.2014.12.030. Epub 2015 Feb 12.

Abstract

Drugs that inhibit the MAPK pathway have therapeutic benefit in melanoma, but responses vary between patients, for reasons that are still largely unknown. Here we aim at explaining this variability using pre- and post-MEK inhibition transcriptional profiles in a panel of melanoma cell lines. We found that most targets are context specific, under the influence of the pathway in only a subset of cell lines. We developed a computational method to identify context-specific targets, and found differences in the activity levels of the interferon pathway, driven by a deletion of the interferon locus. We also discovered that IFNα/β treatment strongly enhances the cytotoxic effect of MEK inhibition, but only in cell lines with low activity of interferon pathway. Taken together, our results suggest that the interferon pathway plays an important role in, and predicts, the response to MAPK inhibition in melanoma. Our analysis demonstrates the value of system-wide perturbation data in predicting drug response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cluster Analysis
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Interferon-alpha / pharmacology*
  • Interferon-beta / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Models, Genetic
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism

Substances

  • Antineoplastic Agents
  • Benzamides
  • Interferon-alpha
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • STAT1 Transcription Factor
  • Interferon-beta
  • mirdametinib
  • Diphenylamine

Associated data

  • GEO/GSE51115