NRG1

Overview

NRG1 (Neuregulin 1) encodes a growth factor ligand that activates ERBB3/ERBB4 receptor tyrosine kinases, feeding into the RAS/MAPK and PI3K/AKT pathways. In cancer, NRG1 fusions (where the kinase-binding domain is preserved) are recurrent and oncogenic across multiple tumor types. NRG1 fusions are strongly enriched in KRAS-wild-type tumors, particularly in pancreatic ductal adenocarcinoma and lung adenocarcinoma.

Alterations observed in the corpus

  • Activating ATP1B1–NRG1 fusion identified by RNA-seq in one MAPK-WT PDAC tumor in a 2,336-patient MSK cohort; NRG1 fusions are nearly exclusive to KRAS-WT tumors and represent a defining molecular feature of the MAPK-WT subtype (2% of all PDAC). PMID:39753968
  • Recurrently SV-affected in rhabdomyosarcoma; implicated in tyrosine kinase signaling and muscle development pathways PMID:24436047
  • NRG1 somatic mutations reported for the first time in gastric cancer; 21/294 cases (~7.1%); EGF-like domain hotspot mutations (p.A221T, p.A225P, p.E223G, p.R224Q, p.S226P); likely activates ERBB4 signaling; defines candidate lapatinib-targetable subset with ERBB4 PMID:25583476
  • CD74-NRG1 fusion identified in 1 LUAD patient; classified as unmatched driver (UMD) alteration in the prospective MSK cohort (860 patients) PMID:28336552

Cancer types (linked)

  • PAAD: NRG1 fusions occur almost exclusively in KRAS-WT PDAC (MAPK-WT subtype). In the MSK 2,336-patient cohort, 2/11 (18%) RNA-sequenced MAPK-WT tumors carried activating BRAF or NRG1 fusions; MAPK-WT patients had significantly better OS than KRAS-mutant patients (HR_adj = 0.69, P = 0.041), a survival advantage that persisted after excluding targeted-therapy recipients. PMID:39753968

Co-occurrence and mutual exclusivity

  • NRG1 fusions nearly exclusive to KRAS-WT tumors; activating MAPK-pathway gene fusions more broadly were exclusive to KRAS-WT (3.2% vs 0.04%, P = 2×10⁻³⁵). PMID:39753968

Therapeutic relevance

  • NRG1-fusion-positive tumors represent a potentially actionable subgroup; afatinib and zenocutuzumab (anti-NRG1 bispecific) have shown activity in NRG1 fusion-positive cancers in other studies (not directly tested in this PDAC cohort). The MAPK-WT PDAC subtype containing NRG1 fusions was explicitly highlighted as warranting separate clinical pathways and trials. PMID:39753968

Open questions

  • Whether the survival advantage of the MAPK-WT subtype is attributable to NRG1 fusions specifically or to the MAPK-WT genomic background more broadly is not resolved; functional MAPK-pathway activity in MAPK-WT tumors without detected fusions needs biochemical confirmation. PMID:39753968

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:24436047

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14.