# Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

Source: https://onco.cc/key-papers/paper-soda-eml4-alk-fusion-nature-2007/  
OnCo record `paper-soda-eml4-alk-fusion-nature-2007` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A small inversion on chromosome 2 fuses two genes and makes a kinase that drives lung cancer. Soda and Mano found it in 5 of 75 tumours, and a drug for it was approved four years later.

## Summary

Soda, Choi, Enomoto and colleagues, with Mano as senior author, showed that a small inversion within chromosome 2p fuses portions of EML4 and ALK in non-small-cell lung cancer cells, that mouse 3T3 fibroblasts forced to express the fusion form transformed foci and subcutaneous tumours, and that the transcript is present in a subset of patients distinct from those with EGFR mutations.

The four years from this paper to crizotinib's approval in 2011 is the shortest interval from the discovery of a driver to an approved drug in solid tumour oncology, and it happened because crizotinib already existed as a MET inhibitor with incidental ALK activity. That accident is the argument for screening existing compound libraries against every new driver.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Nature
- Year: 2007
- DOI: 10.1038/nature05945
- Authors: Soda M, Choi YL, Enomoto M, et al.
- Findings: A small inversion within chromosome 2p forms a fusion gene comprising portions of EML4 and ALK.; Mouse 3T3 fibroblasts expressing the fusion kinase generated transformed foci in culture and subcutaneous tumours in nude mice.; The EML4-ALK fusion transcript was detected in 6.7 percent (5 of 75) of the non-small-cell lung cancer patients examined.; Patients with the fusion were distinct from those harbouring EGFR mutations.; A chromosome 2p inversion fuses EML4 to ALK in lung cancer.; The fusion protein transforms fibroblasts in culture and forms tumours in mice.; Present in 5 of 75 patients, 6.7%, and mutually exclusive with EGFR mutation.
- What it means: The second driver in lung cancer, and the one that proved the first was not a special case. It also established mutual exclusivity as a working assumption: a tumour usually has one driver, so finding it tells you what to give.
- Caveats: 75 tumours from one country; the 6.7 percent figure is higher than the 3 to 5 percent generally found since.; A transforming fusion in fibroblasts is not proof of dependence in a human tumour; that came from the crizotinib trials.; Detection method matters: fluorescence in situ hybridisation, immunohistochemistry and sequencing do not always agree on which tumours are ALK-positive.; Seventy-five patients, so the frequency estimate is imprecise.; The screening method of the day would have missed rarer partners.; Transformation in fibroblasts does not by itself prove dependence in human tumours.

## Sources

- Nature 2007: https://doi.org/10.1038/nature05945
- PubMed: https://pubmed.ncbi.nlm.nih.gov/17625570/
- Soda et al., Nature 2007: identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer: https://doi.org/10.1038/nature05945

## Connected records

- key papers: [Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer](https://onco.cc/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/), [Crizotinib versus chemotherapy in advanced ALK-positive lung cancer](https://onco.cc/key-papers/paper-alk-nsclc-n-engl-j-med-2013/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- cancers: [Adenocarcinoma of the lung](https://onco.cc/cancers/lung-adenocarcinoma/), [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [FISH / ISH (in situ hybridisation)](https://onco.cc/terms/fish/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/), [EGFR](https://onco.cc/targets/egfr/)
- drugs: [Crizotinib](https://onco.cc/drugs/crizotinib/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- bottlenecks: [No incentive to repurpose cheap drugs](https://onco.cc/bottlenecks/b-generic-repurposing/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [The valley of death between lab and product](https://onco.cc/bottlenecks/b-translational-valley/)
- journals: [Nature](https://onco.cc/journals/nature/)
- biomarkers: [ALK fusion (ALK-positive)](https://onco.cc/biomarkers/alk-fusion/)

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