NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis.

Neuregulins (NRGs) are a family of six related physiological ligands all containing a receptor-binding epidermal growth factor (EGF)-like domain that mediate their binding to cellular receptors. Neuregulin-1 (NRG1) is the main physiological ligand to HER3. NRG1 fusion (NRG1+) was first reported in a breast cancer cell line and NRG2 fusions have recently been identified in solid tumors. It is postulated that NRG1 fusions, through mostly transmembrane fusion partners, result in NRG1 being concentrated in proximity to HER3, leading to its constitutive activation and oncogenesis. Recently, a monoclonal antibody that disrupts the binding of NRG1 to HER3 and HER3/HER2 heterodimerization has resulted in NRG1+ tumor shrinkage, suggesting that 'ligand-fusion' may be a novel mechanism of oncogenesis.