Differential contribution for ERK1 and ERK2 kinases in BRAF-triggered phenotypes in adult mouse models.

The BRAF gene is mutated in a plethora of human cancers. The majority of such molecular lesions result in the expression of a constitutively active BRAF variant (BRAF) which continuously bolsters cell proliferation. Although we recently addressed the early effects triggered by BRAF-activation, the specific contribution of ERK1 and ERK2 in BRAF-driven responses in vivo has never been explored. Here we describe the first murine model suitable for genetically dissecting the ERK1/ERK2 impact in multiple phenotypes induced by ubiquitous BRAF-expression. We unveil that ERK1 is dispensable for BRAF-dependent lifespan shortening and for BRAF-driven tumor growth. We show that BRAF-expression provokes an ERK1-independent lymphocyte depletion which does not rely on p21-induced cell cycle arrest and is unresponsive to ERK-chemical inhibition. Moreover, we also reveal that ERK1 is dispensable for BRAF-triggered cytotoxicity in lungs and that ERK-chemical inhibition abrogates some of these detrimental effects, such as DNA damage, in Club cells but not in pulmonary lymphocytes. Our data suggest that ERK1/ERK2 contribution to BRAF-driven phenotypes is dynamic and varies dependently on cell type, the biological function, and the level of ERK-pathway activation. Our findings also provide useful insights into the comprehension of BRAF-driven malignancies pathophysiology as well as the consequences in vivo of novel ERK pathway-targeted anti-cancer therapies.