Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma

Nat Med. 2012 Oct;18(10):1503-10. doi: 10.1038/nm.2941. Epub 2012 Sep 16.

Abstract

The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzimidazoles / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Doxycycline / pharmacology
  • Female
  • Genes, ras
  • Humans
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Middle Aged
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction / drug effects

Substances

  • AZD 6244
  • Benzimidazoles
  • Cyclin-Dependent Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Doxycycline