Data from CD74-NRG1 Fusions Are Oncogenic <i>In Vivo</i> and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization

Abstract

<div>Abstract<p><i>NRG1</i> 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 <i>CD74-NRG1</i> as the first <i>NRG1</i> 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 <i>in vivo</i> 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, <i>NRG1</i> 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.</p></div>