NRG1

  • Neuregulin 1 (NRG1)
  • Gene location: Chromosome 8 (8p12)1

Biology

  • The NRG1 gene encodes the NRG1 protein, which is involved in neural development, myelination, synaptic plasticity, intercellular signaling in the heart and breast, and embryogenesis.1,2
  • The NRG1 protein contains an EGF-like domain that is the ligand for receptor tyrosine kinases (RTKs) in the ERBB family including ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4).1,2
  • NRG1 activates signal transduction by binding to ERBB family RTKs to mediate cell proliferation. Upon binding, ERBB proteins heterodimerize and activate further downstream signaling in MAPK, mTOR, PI3K, and AKT pathways.1-3
  • NRG1 gene fusions lead to overexpression of the EGF-like domain of NRG1 on the cell surface, enhancing its binding ability with ERBB3 (HER3). This promotes heterodimerization between ERBB2 (HER2) and ERBB3 (HER3), triggering the activation of downstream PI3K/AKT and MAPK signaling pathways, which contribute to tumorigenesis.4

Etiology and Epidemiology

  • NRG1 is a large (1.4-Mb) gene, making it more susceptible to fusion events given the size; there are 153 known unique fusion partners.1,5
  • CD74 and SLC3A2 are the most frequently identified upstream fusion partners, with additional partner genes including ATP1B1, CDH1, CLU, CRADD, FUT10, INCENP, KIF22, RBPMS, SLC20A2, VWA8, and XKR6, among others.4-6
  • NRG1 and NRG2 gene fusions are exceptionally rare in solid tumors, with NRG1 fusions occurring at an overall frequency of approximately 0.2% across all solid tumors.4
  • NRG1 gene fusions are most commonly found in gallbladder cancer, pancreatic cancer, renal cell carcinoma, ovarian cancer, non–small cell lung cancer (NSCLC), breast cancer, sarcoma, and bladder cancer.4
  • Identified co-occurring mutations with NRG1 gene fusions include TP53 (54.5%), KRAS, BRAF, PIK3CA, NF1, and NF2, among others.4

NRG1 Testing

When to Test:

  • Molecular profiling with next-generation sequencing (NGS) is recommended at diagnosis for patients with locally advanced/metastatic disease who are candidates for anti-cancer therapy to identify clinically actionable and/or emerging alterations including NRG1 gene fusions.7

Available Testing Methods:

  • RNA sequencing is the preferred method for detecting NRG1 fusions, as DNA-based approaches may miss up to half of cases due to limited sensitivity, variability in intron splicing, and the presence of novel fusion partners.4

Testing Guideline Recommendations:

  • Current NCCN guidelines recommend testing for NRG1 fusions in patients with advanced or metastatic disease for whom zenocutuzumab is being considered.6,7
  • Testing on tumor tissue is preferred; however, cell-free DNA testing can be considered if tumor tissue testing is not feasible.7
  • Molecular testing for patients with locally advanced or metastatic pancreatic cancer should also include assessment of other clinically actionable and/or emerging biomarkers.7

NRG1 Targeted Therapies

Approved Agent(s)

  • On December 4, 2024, the FDA granted accelerated approval to zenocutuzumab-zbco (Bizengri) as the first and only therapy for patients who have pancreatic adenocarcinoma or NSCLC that is advanced, unresectable, or metastatic and harbors an NRG1 gene fusion and who have disease progression on or after prior systemic therapy.8,9

Zenocutuzumab

  • FDA-Approved Indication:
    • Zenocutuzumab is approved for use in adults with advanced, unresectable, or metastatic pancreatic adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.8
  • Mechanism of Action:
    • Zenocutuzumab-zbco is a bispecific antibody that targets the extracellular domains of HER2 and HER3 on cell surfaces, including those of tumor cells. It inhibits HER2:HER3 dimerization and blocks NRG1 from binding to HER3.8
  • Drug information:

References

  1. Gupta B, Gosa Barrett L, Liu SV. NRG1 fusions in NSCLC: being eNRGy conscious. Lung Cancer (Auckl). 2024;15:143-148. doi:10.2147/LCTT.S464626
  2. Kucharczyk T, Nicoś M, Kucharczyk M, Kalinka E. NRG1 gene fusions—what promise remains behind these rare genetic alterations? A comprehensive review of biology, diagnostic approaches, and clinical implications. Cancers. 2024;16(15):2766. doi:10.3390/cancers16152766
  3. Aguirre AJ. Oncogenic NRG1 fusions: a new hope for targeted therapy in pancreatic cancer. Clin Cancer Res. 2019;25(15):4589-4591. doi:10.1158/1078-0432.CCR-19-1280
  4. Xu C, Wang Q, Wang D, et al. Expert consensus on the diagnosis and treatment of NRG1/2 gene fusion solid tumors. Glob Med Genet. 2024;11(1):86-99. doi:10.1055/s-0044-1781457
  5. Kim DW, Schram AM, Hollebecque A, et al. The phase I/II eNRGy trial: zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future Oncol. 2024;20(16):1057-1067. doi:10.2217/fon-2023-0824
  6. Nagasaka M, Ou SHI. NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis. Trends Cancer. 2022;8(3):242-258. doi:10.1016/j.trecan.2021.11.003
  7. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed March 28, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  8. Bizengri. Prescribing information. Partner Therapeutics; 2025. Accessed March 28, 2025. https://www.bizengri.com/pdf/pi.pdf
  9. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma