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^V600E) which continuously bolsters cell proliferation. Although we recently addressed the early effects triggered by BRAF^V600E-activation, the specific contribution of ERK1 and ERK2 in BRAF^V600E-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^V600E-expression. We unveil that ERK1 is dispensable for BRAF^V600E-dependent lifespan shortening and for BRAF^V600E-driven tumor growth. We show that BRAF^V600E-expression provokes an ERK1-independent lymphocyte depletion which does not rely on p21^CIP1-induced cell cycle arrest and is unresponsive to ERK-chemical inhibition. Moreover, we also reveal that ERK1 is dispensable for BRAF^V600E-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^V600E-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^V600E-driven malignancies pathophysiology as well as the consequences in vivo of novel ERK pathway-targeted anti-cancer therapies.

BRAF 基因在多种人类癌症中发生突变。大多数此类分子损伤会导致组成型活性 BRAF 变体 (BRAF ^V600E ) 的表达，从而持续促进细胞增殖。尽管我们最近解决了 BRAF ^V600E激活引发的早期效应，但 ERK1 和 ERK2 在 BRAF ^V600E驱动的体内反应中的具体贡献从未被探索过。在这里，我们描述了第一个适合从基因角度分析 ERK1/ERK2 对普遍存在的 BRAF ^V600E表达诱导的多种表型的影响的小鼠模型。我们发现 ERK1 对于 BRAF ^V600E依赖性寿命缩短和 BRAF ^V600E驱动的肿瘤生长是可有可无的。我们表明，BRAF ^V600E表达会引发不依赖于 ERK1 的淋巴细胞耗竭，这种耗竭不依赖于 p21 ^CIP1诱导的细胞周期停滞，并且对 ERK 化学抑制无反应。此外，我们还揭示了 ERK1 对于 BRAF ^V600E引发的肺细胞毒性是可有可无的，并且 ERK 化学抑制消除了 Club 细胞中的一些有害影响，例如 DNA 损伤，但在肺淋巴细胞中则不然。我们的数据表明，ERK1/ERK2 对 BRAF ^V600E驱动的表型的贡献是动态的，并且根据细胞类型、生物功能和 ERK 通路激活水平而变化。我们的研究结果还为理解 BRAF ^V600E驱动的恶性肿瘤病理生理学以及新型 ERK 通路靶向抗癌疗法的体内后果提供了有用的见解。