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An EGFR ligand promotes EGFR-mutant but not KRAS-mutant lung cancer in vivo

Oncogene volume 37, pages 3894–3908 (2018)Cite this article

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Abstract

EGFR ligands (e.g., EGF and TGFA) have been shown to be clinically associated with poor survival in lung cancer. Since TGFA itself initiates autochthonous tumors in liver, breast, and pancreas but not in the lung in transgenic mice in vivo, it would appear that an EGFR ligand may not initiate but rather promote lung cancer. However, it has not been proven in vivo whether lung cancer is promoted by an EGFR ligand. Using transgenic mouse models conditionally expressing EGFRL858R or KrasG12D with TGFA (an EGFR ligand) in lung epithelium, we determined that TGFA promoted the growth of EGFRL858R-lung tumors in airway regions but not that of KrasG12D-lung tumors. Analysis of TCGA datasets identified ΔNp63 and AGR2 as potential key tumor-promoting regulators, which were highly induced in the TGFA-induced EGFRL858R-lung tumors. The expression of AGR2 was positively correlated with the expression of TGFA in human EGFR-mutant lung adenocarcinomas. The expression of TGFA in human EGFR-mutant lung adenocarcinomas but not in the EGFR wild-type lung adenocarcinoma was associated with poor survival. These results suggest that targeting EGFR ligands may benefit patients who carry EGFR-mutant lung tumors but will not benefit patients with KRAS-mutant lung tumors.

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Acknowledgements

We thank J. Whitsett, H. Varmus, K. Politi, T. Korfhagen, W. Hardie, J. Gokey, and M. Durbin for mice, materials, and discussion.

Funding

This study was supported by the American Lung Association (RG309608), Trustee Award Grant, CF-RDP Pilot & Feasibility Grant, Cincinnati Children’s Hospital Medical Center (YM), the Rotary Foundation Global Grant (KT), AMED (TF), and the Ministry of Education, Science and Culture, Japan (TT, TF, YN, and TN)

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  1. Koichi Tomoshige

    Present address: Departments of Clinical Oncology and Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8501, Japan

Authors and Affiliations

  1. Division of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, 45229-3039, USA

    Koichi Tomoshige, Minzhe Guo, Iris M. Fink-Baldauf, William D. Stuart & Yutaka Maeda

  2. Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8501, Japan

    Tomoshi Tsuchiya & Takeshi Nagayasu

  3. Department of General Surgery, Kawasaki Medical School, Okayama, 701-0192, Japan

    Takuya Fukazawa & Yoshio Naomoto

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Tomoshige, K., Guo, M., Tsuchiya, T. et al. An EGFR ligand promotes EGFR-mutant but not KRAS-mutant lung cancer in vivo. Oncogene 37, 3894–3908 (2018). https://doi.org/10.1038/s41388-018-0240-1

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