title: Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer.
abstract: The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand-receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1, which represent a novel mechanism for ERBB pathway deregulation. These fusions lead to expression and presentation of the EGF-like domain of NRG1 on the cell surface, which binds to ERBB3 in an autocrine and juxtacrine manner, thus inducing the formation of ERBB2-ERBB3 heterodimers, and subsequent activation of the PI3K-AKT and MAPK signaling pathways. These fusion genes were exclusively detected in lung adenocarcinomas of never smokers of the invasive mucinous subtype, which usually presents as a multifocal and unresectable disease, for which no effective treatment exists. Considering the large amount of drugs that target ERBB2 (HER2) and ERBB3 (HER3), and which are currently in different stages of clinical development, detecting and targeting NRG1 fusions in invasive mucinous lung adenocarcinomas may represent a therapeutic opportunity for this aggressive disease.
authors.affiliation: Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyons, France. lynefc30@gmail.com.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.affiliation: Department of Translational Genomics and Pathology, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D020890:Neuregulin-1 / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion