Journal
CANCER DISCOVERY
Volume 4, Issue 4, Pages 415-422Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-0633
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Funding
- Deutsche Krebshilfe as part of the small-cell lung cancer genome-sequencing consortium [109679]
- EU-Framework Programme CURELUNG [HEALTH-F2-2010-258677]
- Deutsche Forschungsgemeinschaft [TH1386/3-1, SFB832]
- German Ministry of Science and Education (BMBF) as part of the NGFNplus program [01GS08101]
- Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program
- Stand Up To Cancer Innovative Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-IRG60109]
- DFG Excellence Cluster ImmunoSensation
- Italian Ministry of Health [RC1303LO57]
- GR Program [2010-2316264]
- 5 x 1000 voluntary contributions
- Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan
- IWT [110431]
- Belgium government agency for Innovation by Science and Technology (IWT)
- Agiradom and French Health Ministry (PPHRC)
- Grants-in-Aid for Scientific Research [22134005] Funding Source: KAKEN
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We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III- ss 3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion ( P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. SIGNIFICANCE: CD74-NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415- 22. (c) 2014 AACR.
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