KRAS is one of the most frequently mutated oncogenes, especially in lung cancers. Targeting of KRAS directly or the downstream effector signaling machinery is of prime interest in treating lung cancers. Here, we uncover that ERK3, a ubiquitously expressed atypical MAPK, is required for KRAS-mediated NSCLC tumors. ERK3 is highly expressed in lung cancers, and oncogenic KRAS led to the activation and stabilization of the ERK3 protein. In particular, phosphorylation of serine 189 in the activation motif of ERK3 is significantly increased in lung adenocarcinomas in comparison to adjacent normal controls in patients. Loss of ERK3 prevents the anchorage-independent growth of KRAS G12C-transformed human bronchial epithelial cells. We further find that loss of ERK3 reduces the oncogenic growth of KRAS G12C-driven NSCLC tumors in vivo and that the kinase activity of ERK3 is required for KRAS-driven oncogenesis in vitro. Our results demonstrate an obligatory role for ERK3 in NSCLC tumor progression and suggest that ERK3 kinase inhibitors can be pursued for treating KRAS G12C-driven tumors.

KRAS 是最常发生突变的癌基因之一，尤其是在肺癌中。直接靶向 KRAS 或下游效应信号机制是治疗肺癌的主要目标。在这里，我们发现 ERK3，一种普遍表达的非典型 MAPK，是 KRAS 介导的 NSCLC 肿瘤所必需的。ERK3 在肺癌中高度表达，致癌 KRAS 导致 ERK3 蛋白的激活和稳定。特别是，与患者的相邻正常对照相比，肺腺癌中 ERK3 激活基序中丝氨酸 189 的磷酸化显着增加。ERK3 的缺失阻止了 KRAS G12C 转化的人支气管上皮细胞不依赖锚定的生长。我们进一步发现 ERK3 的缺失降低了 KRAS G12C 驱动的 NSCLC 肿瘤在体内的致癌生长，并且 ERK3 的激酶活性是 KRAS 驱动的体外肿瘤发生所必需的。我们的结果证明了 ERK3 在 NSCLC 肿瘤进展中的强制性作用，并表明 ERK3 激酶抑制剂可用于治疗 KRAS G12C 驱动的肿瘤。