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

Abstract

Mutationally activated BRAF^V600E (BRAF^VE) is detected in ∼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. BRaf^CA 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. BRaf^VE expression initially induced proliferation that was followed by growth arrest bearing certain hallmarks of senescence. Consistent with Ink4a/Arf and TP53 tumor suppressor function, BRaf^VE expression combined with mutation of either locus led to cancer progression.

Keywords

• BRaf
• mouse model
• lung tumors
• senescence