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Updated: Oct 1, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization
Lisa Werr1, Dennis Plenker1,2,3, Marcel A Dammert1,2,3
1Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Abstract:
NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1-expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.
Insights
NRG1 gene fusions drive tumor development by activating ERBB2:ERBB3 signaling. This creates an oncogene dependency, making NRG1 fusion-positive cancers responsive to targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- NRG1 fusions are recurrent genetic alterations found in lung and pancreatic cancers.
- CD74-NRG1 was the first identified NRG1 fusion, with more partners subsequently discovered.
Purpose of the Study:
- To establish the first CD74-NRG1 transgenic mouse model.
- To investigate the in vivo oncogenic mechanisms of CD74-NRG1 fusions.
- To explore therapeutic strategies for NRG1 fusion-driven cancers.
Main Methods:
- Development of a CD74-NRG1 transgenic mouse model.
- Analysis of tumor development and cellular proliferation in vivo.
- Investigation of ERBB2:ERBB3 heterodimerization as a downstream signaling event.
Main Results:
- Ubiquitous CD74-NRG1 expression induced high-frequency tumor development in mice.
- CD74-NRG1 directly binds ERBB3, driving ERBB2:ERBB3 heterodimerization and transformation.
- NRG1 fusion-expressing cells exhibited ligand-independent proliferation, indicating oncogene addiction.
Conclusions:
- NRG1 gene fusions act as driver oncogenes, creating dependency on the NRG1 pathway.
- Targeting the ERBB2:ERBB3 receptor pathway shows promise for treating NRG1 fusion-positive cancers.
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