{"entity":{"id":"paper-soda-eml4-alk-fusion-nature-2007","kind":"paper","name":"Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer","aka":[],"tldr":"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.\n\nThe 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.","asOf":"2026-09-25","links":[{"label":"Nature 2007","url":"https://doi.org/10.1038/nature05945"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/17625570/"},{"label":"Soda et al., Nature 2007: identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer","url":"https://doi.org/10.1038/nature05945"}],"tags":["lung-evidence"],"related":["paper-kwak-crizotinib-alk-nsclc-nejm-2010","paper-alk-nsclc-n-engl-j-med-2013","targeted-therapy-roadmap"],"cancers":["lung-cancer","nsclc","alk-positive-nsclc","lung-adenocarcinoma"],"sections":["targeted-therapy","drug-discovery"],"technologies":["fish","ihc","ngs","kinase-inhibitors"],"targets":["alk","egfr"],"drugs":["crizotinib"],"companies":[],"institutions":[],"pathways":["rtk-activation","nsclc-signalling"],"terms":["driver-mutation","oncogene-addiction","gene-fusion"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-translational-valley","b-generic-repurposing"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2007,"doi":"10.1038/nature05945","pmid":"17625570","authors":"Soda M, Choi YL, Enomoto M, et al.","paperType":"basic","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."],"whatItMeans":"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."],"changedPractice":true,"participants":75},"route":"/key-papers/paper-soda-eml4-alk-fusion-nature-2007/","neighbours":{"paper":[{"id":"paper-kwak-crizotinib-alk-nsclc-nejm-2010","kind":"paper","name":"Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer","route":"/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/"},{"id":"paper-alk-nsclc-n-engl-j-med-2013","kind":"paper","name":"Crizotinib versus chemotherapy in advanced ALK-positive lung cancer","route":"/key-papers/paper-alk-nsclc-n-engl-j-med-2013/"}],"roadmap":[{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/lung-cancer-evidence-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"cancer":[{"id":"lung-adenocarcinoma","kind":"cancer","name":"Adenocarcinoma of the lung","route":"/cancers/lung-adenocarcinoma/"},{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"fish","kind":"term","name":"FISH / ISH (in situ hybridisation)","route":"/terms/fish/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"drug":[{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"bottleneck":[{"id":"b-generic-repurposing","kind":"bottleneck","name":"No incentive to repurpose cheap drugs","route":"/bottlenecks/b-generic-repurposing/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-translational-valley","kind":"bottleneck","name":"The valley of death between lab and product","route":"/bottlenecks/b-translational-valley/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}],"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"}]}}