Modelling Vemurafenib Resistance in Melanoma Reveals a Strategy to Forestall Drug Resistance

Nature. 2013 Feb 14;494(7436):251-5. doi: 10.1038/nature11814. Epub 2013 Jan 9.

Abstract

Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)→MEK→ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Administration Schedule
  • Drug Resistance, Neoplasm / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Indoles / administration & dosage*
  • Indoles / adverse effects*
  • Indoles / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins B-raf / chemistry
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Subcutaneous Tissue
  • Sulfonamides / administration & dosage*
  • Sulfonamides / adverse effects*
  • Sulfonamides / pharmacology
  • Time Factors
  • Vemurafenib
  • Xenograft Model Antitumor Assays

Substances

  • Indoles
  • Sulfonamides
  • Vemurafenib
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases