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A new mouse model to explore the initiation, progression, and therapy of BRAF(V600E)-induced lung tumors

  • Author(s): Dankort, David
  • Filenova, Elena
  • Collado, Manuel
  • Serrano, Manuel
  • Jones, Kirk
  • McMahon, Martin
  • et al.
Abstract

Mutationally activated BRAF(V600E) (BRAF(VE)) is detected in similar to 6% of human malignancies and promotes sustained MEK1/2-ERK1/2 pathway activation. We have designed BRaf(CA) mice to express normal BRaf prior to Cre-mediated recombination after which BRaf(VE) is expressed at physiological levels. BRafCA mice infected with an Adenovirus expressing Cre recombinase developed benign lung tumors that only rarely progressed to adenocarcinoma. Moreover, BRaf(VE)-induced lung tumors were prevented by pharmacological inhibition of MEK1/2. BRafVE expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRafVE expression combined with mutation of either locus led to cancer progression.

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