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Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.

  • Author(s): Dankort, David;
  • Curley, David P;
  • Cartlidge, Robert A;
  • Nelson, Betsy;
  • Karnezis, Anthony N;
  • Damsky, William E;
  • You, Mingjian J;
  • DePinho, Ronald A;
  • McMahon, Martin;
  • Bosenberg, Marcus
  • et al.

Published Web Location

https://doi.org/10.1038/ng.356
Abstract

Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.

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