NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer

Cancer Discov. 2018 Sep;8(9):1087-1095. doi: 10.1158/2159-8290.CD-18-0036. Epub 2018 May 25.


We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087-95. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Gene Expression Profiling / methods
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Middle Aged
  • Neuregulin-1 / genetics*
  • Oncogene Proteins, Fusion / genetics
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Precision Medicine
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / pharmacology
  • Translocation, Genetic
  • Treatment Outcome
  • Whole Genome Sequencing / methods
  • Xenograft Model Antitumor Assays
  • Young Adult


  • KRAS protein, human
  • NRG1 protein, human
  • Neuregulin-1
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)