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

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.

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors

“…24 Studies using CD74-NRG1 transgenic mouse models have shown that the proliferation of CD74-NRG1 cells is carcinogenic and accompanied by increased protein transcription levels of ERBB2 and ERBB3, indicating that NRG1 gene fusion drives tumor development. 25…”

“… 24 Studies using CD74 - NRG1 transgenic mouse models have shown that the proliferation of CD74 - NRG1 cells is carcinogenic and accompanied by increased protein transcription levels of ERBB2 and ERBB3, indicating that NRG1 gene fusion drives tumor development. 25 NRG1 gene fusion is the first potential therapeutic oncogenic driver mutation specifically associated with a subtype of lung adenocarcinoma and is predominantly found in nonsmoking patients, in contrast to the tobacco-associated KRAS gene mutation. 24 In a transcriptome sequencing study of 25 never-smoking lung adenocarcinoma patients, one case of CD74 - NRG1 gene fusion was identified in a patient with invasive mucinous subtype.…”

Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma

“…Neuregulin 1 ( NRG1 ) is a soluble ligand that ordinarily is released from cells and acts as a paracrine messenger [ 90 , 91 ]. NRG1 binds to HER3, promoting HER2/HER3 dimerization and PI3K/AKT/mTOR signaling [ 90 , 91 ]. NRG1 fusions are oncogenic drivers in PDAC and account for 1.3% of KRAS WT cases [ 63 , 92 ].…”

“…NRG1 fusions are oncogenic drivers in PDAC and account for 1.3% of KRAS WT cases [ 63 , 92 ]. Mechanistically, NRG1 fusion proteins tether the NRG1 to the plasma membrane, resulting in hyperactivation of HER3 [ 90 , 91 ]. Zenocutuzumab, an investigational bispecific antibody targeting HER2 and HER3, has shown promising efficacy in patients with KRAS WT PDAC with NRG1 fusions [ 93 ].…”

Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer

“…NRG1 is selectively expressed in the endocardium and myocardial microvessels. Recent research has revealed its intricate participation in various tumors, yielding molecular modifications across multiple tumor-associated signaling pathways ( 4 , 5 ). The intricate interplay between NRG1 and tumorigenesis has garnered substantial attention, particularly in the context of NSCLC.…”