Targeting BRAFV600E in an Inducible Murine Model of Melanoma

Am J Pathol. 2012 Sep;181(3):785-94. doi: 10.1016/j.ajpath.2012.06.002. Epub 2012 Jul 11.

Abstract

The MAP kinase and PI3 kinase pathways have been identified as the most common pathways that mediate oncogenic transformation in melanoma, and the majority of compounds developed for melanoma treatment target one or the other of these pathways. In addition to such targeted therapies, immunotherapeutic approaches have shown promising results. A combination of these two treatment modalities could potentially result in further improvement of treatment outcome. To preclinically identify efficient treatment combinations and to optimize therapy protocols in terms of sequence and timing, mouse models will be required. We have crossed and characterized the Tyr::CreER(T2);PTEN(F-/-);BRAF(F-V600E/+) inducible melanoma model on a C57BL/6J background. Tumors from this model harbor the BRAF(V600E) mutation and are PTEN-deficient, making them highly suitable for the testing of targeted therapies. Furthermore, we crossed the model onto this specific background for use in immunotherapy studies, because most experiments in this field have been performed in C57BL/6J mice. Selective inhibition of BRAF(V600E) by PLX4720 treatment of melanoma-bearing mice resulted in a strong decrease of tumor outgrowth. Furthermore, the inducible melanomas had immune cell infiltrates similar to those found in human melanoma, and tumor-infiltrating lymphocytes could be cultured from these tumors. Our data indicate that the C57BL/6J Tyr::CreER(T2);PTEN(F-/-);BRAF(F-V600E/+) melanoma model could be used as a standard model in which targeted and immunotherapy combinations can be tested in a high-throughput manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Transformation, Neoplastic / pathology
  • Disease Models, Animal
  • Drug Administration Routes
  • Humans
  • Indoles / administration & dosage
  • Indoles / blood
  • Integrases / metabolism
  • Lymphatic Metastasis / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Melanoma / blood
  • Melanoma / immunology
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy*
  • Mutation / genetics
  • PTEN Phosphohydrolase / genetics
  • Proto-Oncogene Proteins B-raf / genetics*
  • Skin Neoplasms / blood
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology*
  • Sulfonamides / administration & dosage
  • Sulfonamides / blood
  • Time Factors

Substances

  • Indoles
  • PLX 4720
  • Sulfonamides
  • Braf protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Cre recombinase
  • Integrases
  • PTEN Phosphohydrolase
  • Pten protein, mouse