文章：

ERK3/MAPK6是KRAS介导的NSCLC肿瘤发生所必需的

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis 

原文发布日期：2020-10-17

英文摘要：

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. 

摘要翻译： 

KRAS是最常发生突变的癌基因之一，尤其在肺癌中。直接靶向KRAS或其下游效应信号机制已成为肺癌治疗的重要方向。本研究发现，ERK3（一种广泛表达的非典型MAPK激酶）是KRAS介导的非小细胞肺癌（NSCLC）发生所必需的分子。ERK3在肺癌中高表达，致癌性KRAS可导致ERK3蛋白的激活与稳定化。特别值得注意的是，与患者癌旁正常组织相比，肺腺癌中ERK3激活基序第189位丝氨酸（S189）的磷酸化水平显著升高。敲除ERK3可抑制KRAS G12C突变转化的人支气管上皮细胞的锚定非依赖性生长。进一步研究发现，ERK3缺失能降低KRAS G12C驱动型NSCLC肿瘤的体内致癌性生长，且ERK3的激酶活性是KRAS驱动体外致癌作用所必需的。我们的研究结果揭示了ERK3在NSCLC肿瘤进展中的关键作用，表明ERK3激酶抑制剂有望用于治疗KRAS G12C驱动型肿瘤。

原文链接：

ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis