Nrg1, or neuregulin-1, is a significant gene encoding a ligand that binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways [2,3,4]. This activation of the ErbB-mediated pathway is of great biological importance, potentially driving tumorigenesis in multiple solid tumors [1].

Oncogenic Nrg1 fusions are rare across different cancer types, with an incidence of <1% in most cases, but are more prevalent (≈10%-30%) in invasive mucinous adenocarcinomas (IMAs) of the lung [1]. These fusions, such as CD74-Nrg1 and others with partners like ATP1B1, SDC4, and RBPMS, result in constitutive activation of HER3 and oncogenesis [1,4]. In a phase 2 clinical study, the bispecific antibody zenocutuzumab targeting HER2 and HER3 showed efficacy in patients with advanced Nrg1 fusion-positive cancer, including non-small-cell lung cancer and pancreatic cancer, with mainly low-grade adverse events [2]. In addition, pre-clinical studies in Nrg1 fusion-positive isogenic and patient-derived cell lines and xenograft models demonstrated that zenocutuzumab inhibited HER3 and AKT phosphorylation, induced apoptosis, and inhibited growth [3].

In conclusion, Nrg1 plays a crucial role in activating growth-promoting pathways, especially when fused with other genes. The study of Nrg1 fusion-positive cancers using various research models, including in vivo models like xenograft models, has provided insights into its role in tumorigenesis. The development of targeted therapies such as zenocutuzumab for Nrg1 fusion-positive cancers shows the potential of understanding Nrg1's function in improving cancer treatment [2,3].