Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

• Published in: Oncogene Vol. 32; no. 34; pp. 4034 - 4042
• Main Authors: Sunaga, N, Kaira, K, Imai, H, Shimizu, K, Nakano, T, Shames, D S, Girard, L, Soh, J, Sato, M, Iwasaki, Y, Ishizuka, T, Gazdar, A F, Minna, J D, Mori, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.08.2013; Nature Publishing Group
• Subjects: Adenocarcinoma; Aged; Apoptosis; Apoptosis - genetics; Butadienes - pharmacology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Care and treatment; Cell Biology; Cell Line; Cell Line, Tumor; Cellular proteins; Cellular signal transduction; Copy number; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Epidermal growth factor receptors; Epiregulin; Epithelial cells; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene mutations; Genetic aspects; Genotype & phenotype; Health aspects; Human Genetics; Humans; Immunohistochemistry; Internal Medicine; K-Ras protein; Kaplan-Meier Estimate; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Multivariate analysis; Mutants; Mutation; Nitriles - pharmacology; Non-small cell lung carcinoma; Oncology; original-article; Phenotype; Phenotypes; Physiological aspects; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); Pyrazoles - pharmacology; Pyridazines - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; Receptor, Epidermal Growth Factor - genetics; Risk factors; RNA Interference; Signal transduction; siRNA; Small cell lung carcinoma; Therapeutic applications; Therapeutic targets; Transcription; United States; Japan; KRAS; therapeutic target; NSCLC; EREG
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.402

KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified epiregulin ( EREG ) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS -mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS . In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS , BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS / BRAF / EGFR . Small interfering RNAs (siRNAs) targeting mutant KRAS , but not an siRNA targeting wild-type KRAS , significantly reduced EREG expression in KRAS -mutant and EREG -overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression significantly correlated with KRAS expression or KRAS copy number in KRAS -mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS -mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS -mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.