Bogucka Katarzyna, Marini Federico, Rosigkeit Sebastian, Schloeder Janine, Jonuleit Helmut, David Kerstin, Schlackow Margarita, Rajalingam Krishnaraj
Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
Cancer Gene Ther. 2021 May;28(5):359-374. doi: 10.1038/s41417-020-00245-w. Epub 2020 Oct 17.
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是最常发生突变的致癌基因之一，尤其是在肺癌中。直接靶向KRAS或其下游效应信号机制是治疗肺癌的主要研究方向。在此，我们发现ERK3，一种广泛表达的非典型丝裂原活化蛋白激酶（MAPK），是KRAS介导的非小细胞肺癌（NSCLC）肿瘤所必需的。ERK3在肺癌中高表达，致癌性KRAS导致ERK3蛋白的激活和稳定。特别是，与患者相邻正常对照相比，肺腺癌中ERK3激活基序中丝氨酸189的磷酸化显著增加。ERK3的缺失阻止了KRAS G12C转化的人支气管上皮细胞的非锚定依赖性生长。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的激酶活性是体外KRAS驱动的肿瘤发生所必需的。我们的结果证明了ERK3在NSCLC肿瘤进展中的关键作用，并表明可以探索ERK3激酶抑制剂来治疗KRAS G12C驱动的肿瘤。
