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ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis

A Correction to this article was published on 09 November 2020

This article has been updated


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.

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Fig. 1: ERK3 expression in NSCLC.
Fig. 2: KRAS overexpression leads to upregulation and stabilization of ERK3 protein.
Fig. 3: Role of ERK3 in anchorage-independent growth of SALEB and SAKRAS cells.
Fig. 4: ERK3-depleted G12C-driven NSCLC cells exhibit a decrease in anchorage-independent growth.
Fig. 5: Loss of ERK3 negatively affects oncogenic growth of KRAS G12C-driven NSCLC tumors in vivo.
Fig. 6: Schematic representation.

Change history

  • 30 October 2020

    This Article was originally published under an Open Access licence [CC BY 4.0] in error. It should have been published under Nature Research’s License to Publish. The PDF and HTML versions of the Article have been corrected accordingly.

  • 09 November 2020

    A Correction to this paper has been published:


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We thank Stefanie Wenzel for excellent technical assistance. This work is supported from the grants from Else Kroener Fresenius Stiftung; MERCK (project ID-ERK-KR), CRC 1292, TP12, and Forschungszentrum für Immuntherapie of the University Medical Center Mainz to KR. We thank Dr. Daniela Hoeller for critical reading of the paper. We thank Dr. Bernd Gromol for his help with the H scoring and Dr. Jonathan Woodsmith for help with the analysis of Omics data, KR is supported through a Heisenberg professorship of the DFG (RA1739/4-1). We would like to thank the Translational oncology team of MERCK for their valuable inputs and advise. We thank Dr. Christiane Schoenfeld for analyses of the animal experiments.

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KB designed and performed most of the experiments as well as analyzed/interpreted the data prepared Figures and wrote the paper. FM performed Bioinformatic analyses. KD contributed to the staining and analyses of NSCLC tissue microarray. JS, HJ, and SR contributed to xenografts experiments. MS contributed to the bioinformatic analysis of RNA sequencing. KR contributed to the conception, design, analyzed/interpreted the data, and supervised the study. KB and KR wrote the paper with input from all authors.

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Correspondence to Krishnaraj Rajalingam.

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Bogucka, K., Marini, F., Rosigkeit, S. et al. ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis. Cancer Gene Ther 28, 359–374 (2021).

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