# CD74-NRG1 fusions in lung adenocarcinoma

Source: https://onco.cc/key-papers/paper-fernandez-cuesta-cd74-nrg1-fusion-lung-cancer-discov-2014/  
OnCo record `paper-fernandez-cuesta-cd74-nrg1-fusion-lung-cancer-discov-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading the active genes of 25 lung cancers from people who had never smoked turned up a fusion that does something unusual: instead of switching on a receptor directly, it hangs the receptor's own trigger on the outside of the cell.

## Summary

A novel somatic gene fusion, CD74-NRG1, was discovered by transcriptome sequencing of 25 lung adenocarcinomas from never smokers. Screening 102 lung adenocarcinomas negative for known oncogenic alterations found four additional fusion-positive tumours, all of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-beta3, providing the ligand for ERBB2-ERBB3 receptor complexes. ERBB2 and ERBB3 expression was high in the index case, phospho-ERBB3 expression was specific to fusion-positive tumours, and ectopic expression of the fusion in lung cancer cells expressing both receptors activated ERBB3 and the PI3K-AKT pathway and increased colony formation in soft agar.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Cancer Discovery
- Year: 2014
- DOI: 10.1158/2159-8290.CD-13-0633
- Authors: Fernandez-Cuesta L, Plenker D, Osada H, et al.
- Findings: CD74-NRG1 fusions discovered in never-smoker lung adenocarcinoma.; All additional cases were of the invasive mucinous subtype, a histology with no effective treatment.; The fusion supplies a ligand for HER2-HER3 dimers rather than activating a kinase directly.; Fusion-positive tumours show specific phospho-ERBB3 expression.
- What it means: It identified a driver in the one lung histology that had none, and it defined a mechanism, ligand presentation, that requires an antibody against the receptor pair rather than a kinase inhibitor.
- Caveats: Very small numbers: one index case and four confirmations.; Requires RNA sequencing to detect, so prevalence from DNA panels is an undercount.; No approved therapy in this class at the time of publication.

## Sources

- Fernandez-Cuesta et al., Cancer Discov 2014: CD74-NRG1 fusions in invasive mucinous lung adenocarcinoma: https://doi.org/10.1158/2159-8290.CD-13-0633
- PubMed: https://pubmed.ncbi.nlm.nih.gov/24469108/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [RNA sequencing & expression profiling](https://onco.cc/technologies/rna-seq/)
- targets: [HER2](https://onco.cc/targets/her2/), [NRG1](https://onco.cc/targets/nrg1/)
- pathways: [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Gene fusion](https://onco.cc/terms/gene-fusion/)
- people: [Roman Thomas](https://onco.cc/people/roman-thomas/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)
- biomarkers: [NRG1 gene fusion](https://onco.cc/biomarkers/nrg1-fusion/)

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