Werr, Lisa ORCID: 0000-0002-3697-4136, Plenker, Dennis, Dammert, Marcel A., Lorenz, Carina, Bragelmann, Johannes, Tumbrink, Hannah L., Klein, Sebastian, Schmitt, Anna, Buttner, Reinhard, Persigehl, Thorsten, Shokat, Kevan M., Wunderlich, F. Thomas, Schram, Alison M., Peifer, Martin ORCID: 0000-0002-5243-5503, Sos, Martin L., Reinhardt, H. Christian and Thomas, Roman K. (2022). CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization. Mol. Cancer Ther., 21 (5). S. 821 - 831. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-8514

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Werr, LisaUNSPECIFIEDorcid.org/0000-0002-3697-4136UNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dammert, Marcel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bragelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buttner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shokat, Kevan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schram, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-692222
DOI: 10.1158/1535-7163.MCT-21-0820
Journal or Publication Title: Mol. Cancer Ther.
Volume: 21
Number: 5
Page Range: S. 821 - 831
Date: 2022
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-8514
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROWTH-FACTOR; LUNG-CANCER; CELL-LINE; NRG1; RESISTANCE; MODELSMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69222

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