CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
04 05 2022
04 05 2022
Historique:
received:
05
10
2021
revised:
21
12
2021
accepted:
15
02
2022
pubmed:
6
3
2022
medline:
6
5
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35247925
pii: 681959
doi: 10.1158/1535-7163.MCT-21-0820
pmc: PMC9377738
doi:
Substances chimiques
NRG1 protein, human
0
Neuregulin-1
0
Nrg1 protein, mouse
0
ERBB2 protein, human
EC 2.7.10.1
ERBB3 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Receptor, ErbB-3
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
821-830Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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