NRG1 stands for Neuregulin 1, a gene that encodes ligands for ERBB family receptors, particularly ERBB3 and ERBB4. These receptors are part of the EGFR (epidermal growth factor receptor) signaling pathway, which is crucial for cell growth, survival, and differentiation. When fused with other genes, NRG1 can become aberrantly expressed, leading to constitutive activation of ERBB-mediated signaling pathways, which promote cell proliferation, survival, and metastasis.1
NRG1 fusions are rare but increasingly recognized across several cancer types, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma, breast cancer, and salivary gland tumors.2 In particular, invasive mucinous adenocarcinoma (IMA) of the lung exhibits a higher prevalence of these fusions, reported in up to 27% of cases.3 The most common fusion partners include CD74, SLC3A2, and VAMP2, which provide a strong promoter to drive overexpression of the NRG1 fusion gene.4
The oncogenic potential of NRG1 fusions arises primarily from ligand-dependent activation of ERBB3, which dimerizes with ERBB2, triggering downstream pathways such as PI3K/AKT and MAPK/ERK.5 This mode of activation distinguishes NRG1 fusion-driven cancers from those harboring activating mutations or amplifications in ERBB family genes, suggesting a distinct therapeutic vulnerability. As precision oncology evolves, NRG1 fusions represent a compelling target for personalized therapy across multiple tumor types.
Understanding the Role of NRG1 in Cancer Pathogenesis
Table of Drugs
Emerging therapies targeting the ERBB2/ERBB3 pathway have shown promise in early trials. Agents such as zenocutuzumab, a bispecific antibody targeting HER2 and HER3, have demonstrated encouraging clinical activity in patients with NRG1 fusion–positive cancers. Several other agents targeting the ERBB pathway are under investigation, further underscoring the importance of identifying NRG1 alterations.
|
Drug |
Type |
Target |
Status |
Indications |
|
Bizengri (Zenocutuzumab) |
Bispecific antibody |
HER2/HER3 |
FDA approved (2024) |
NRG1 fusion+ NSCLC, pancreatic cancer |
|
Seribantumab |
Monoclonal antibody |
HER3 |
In development |
NRG1 fusion+ solid tumors |
|
NGR-hTNF |
Recombinant protein |
Tumor vasculature |
In development |
Various solid tumors (experimental) |
