CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

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.

Automated summary

NRG1 fusions are recurrent somatic genome alterations that occur in various types of tumors, and they have potentially actionable genetic effects on cancers such as invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas. This study presents the first CD74-NRG1 transgenic mouse model and provides evidence that ubiquitous expression of the CD74-NRG1 fusion protein leads to frequent tumor development in vivo. The study also demonstrates that CD74-NRG1 binding to ERBB3 and subsequent ERBB2:ERBB3 heterodimerization is a mechanistic event in the transformation process. NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency, and patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.