title: Epiregulin as a therapeutic target in non-small-cell lung cancer.
abstract: Epiregulin (EREG) belongs to the ErbB family of ligands. EREG binds to EGFR and ErbB4 receptor and stimulates homodimers of EGFR and ErbB4 in addition to all possible heterodimeric ErbB complexes, resulting in the activation of downstream signaling pathways. EREG is overexpressed in various human cancers and has been implicated in tumor progression and metastasis. Oncogenic activation of the MEK/ERK pathway plays a central role in the regulation of EREG expression. Non-small-cell lung cancers (NSCLCs) harboringKRAS,BRAF, orEGFRmutations overexpress EREG, and abrogation of such mutations or inhibition of MEK or ERK downregulates the expression of EREG. Elevated EREG expression in NSCLC is associated with aggressive tumor phenotypes and unfavorable prognosis, especially in oncogenic KRAS-driven lung adenocarcinomas. The finding that attenuation of EREG inhibits cell growth and induces apoptosis inKRAS-mutant and EREG-overexpressing NSCLC cell lines suggests that targeting EREG might be a treatment option forKRAS-mutant NSCLC, although further studies are necessary to elucidate its therapeutic value. These observations suggest that oncogenic mutations in theEGFR,KRAS, orBRAFgenes induce EREG upregulation through the activation of MEK/ERK pathway in NSCLC cells, whereas overproduced EREG stimulates the EGFR/ErbB receptors and activates multiple downstream signaling pathways, leading to tumor progression and metastasis of these oncogene-driven NSCLCs. This paper reviews the current understanding of the oncogenic role of EREG and highlights its potential as a therapeutic target for NSCLC.
authors.affiliation: Oncology Center, Gunma University Hospital; Department of Medicine and Molecular Science.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sunaga
authors.affiliation: Department of Medicine and Molecular Science; Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
keywords: KRAS mutation; NSCLC; epiregulin; therapeutic target