{"entity":{"id":"paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","kind":"paper","name":"Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data","aka":[],"tldr":"Small-cell lung cancer, treated as one disease for fifty years, is at least four. The subtypes are named after the transcription factor each one leans on: ASCL1, NeuroD1, YAP1 and POU2F3.","summary":"Rudin, Poirier, Byers, Dive and eighteen colleagues proposed a working nomenclature for small-cell lung cancer subtypes defined by the relative expression of four key transcription regulators, ASCL1, NeuroD1, YAP1 and POU2F3, synthesising evidence from primary human tumours, patient-derived xenografts, cell lines and genetically engineered mouse models.\n\nA consensus perspective rather than a study, and it is on this list because of what it enabled: once the subtypes had names, trials could be designed around them, and the therapeutic vulnerabilities that differ between them (DLL3 in ASCL1-high disease, PARP and checkpoint sensitivity elsewhere) became testable propositions rather than post hoc observations.","asOf":"2026-09-25","links":[{"label":"Nat Rev Cancer 2019","url":"https://doi.org/10.1038/s41568-019-0133-9"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30926931/"},{"label":"Author correction (2019)","url":"https://europepmc.org/article/MED/31175338"},{"label":"Rudin et al., Nat Rev Cancer 2019: the molecular subtypes of small-cell lung cancer, a synthesis of human and mouse data","url":"https://doi.org/10.1038/s41568-019-0133-9"}],"tags":["lung-evidence"],"related":["paper-george-sclc-genomic-profiles-nature-2015","paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023","idea-sclc-subtype-directed"],"cancers":["lung-cancer","sclc","limited-stage-sclc","extensive-stage-sclc"],"sections":["drug-discovery","diagnostics"],"technologies":["rna-seq","organoids"],"targets":["dll3","ascl1","yap1","myc-gene","mycl"],"drugs":[],"companies":[],"institutions":["mskcc","md-anderson"],"pathways":["sclc-signalling","lineage-plasticity-neuroendocrine","transcription-addiction","myc"],"terms":["histology","driver-mutation"],"trials":[],"people":["charles-rudin"],"bottlenecks":["b-rare-cancers","b-biomarker-validation","b-trial-design"],"keyPapers":[],"journals":["nature-reviews-cancer"],"dependsOn":[],"notes":[],"journal":"Nature Reviews Cancer","year":2019,"doi":"10.1038/s41568-019-0133-9","pmid":"30926931","authors":"Rudin CM, Poirier JT, Byers LA, et al.","paperType":"review","findings":["Several independent lines of evidence converge on a model of small-cell lung cancer subtypes defined by differential expression of ASCL1, NeuroD1, YAP1 and POU2F3.","The authors propose a working nomenclature for these subtypes and argue that defining their unique therapeutic vulnerabilities should focus and accelerate therapeutic research.","Four subtypes of small-cell lung cancer defined by ASCL1, NeuroD1, YAP1 and POU2F3 expression.","The subtypes carry different therapeutic vulnerabilities.","A common nomenclature was proposed and has since been adopted."],"whatItMeans":"The organising framework for every small-cell lung cancer trial designed since. It is also why the slow progress in the disease is now attributed to treating four diseases as one rather than to the biology being intractable.","caveats":["A perspective piece proposing a nomenclature, not a validation study; subtype assignment is not a routine clinical test.","Subtypes are transcriptional states, and tumours can shift between them under treatment, so a baseline assignment may not hold.","No randomised trial has yet assigned treatment by subtype and shown benefit.","A synthesis and proposal rather than a primary dataset.","The YAP1 subtype has since been hard to confirm in patient samples.","No assay is approved and no trial has randomised on subtype."],"changedPractice":false},"route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/","neighbours":{"paper":[{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-dll3-sclc-clin-cancer-res-2019","kind":"paper","name":"Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study","route":"/key-papers/paper-dll3-sclc-clin-cancer-res-2019/"},{"id":"paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011","kind":"paper","name":"Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors","route":"/key-papers/paper-sequist-genotypic-histological-evolution-egfr-resistance-sci-transl-med-2011/"},{"id":"paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023","kind":"paper","name":"Tarlatamab for patients with previously treated small-cell lung cancer","route":"/key-papers/paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023/"}],"idea":[{"id":"idea-lung-small-cell-platform-with-shared-controls-and-subtypes","kind":"idea","name":"Run small-cell lung cancer as one platform with shared controls and subtype stratification","route":"/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/"},{"id":"idea-sclc-subtype-directed","kind":"idea","name":"Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed)","route":"/ideas/idea-sclc-subtype-directed/"}],"cancer":[{"id":"extensive-stage-sclc","kind":"cancer","name":"Extensive-stage small-cell lung cancer","route":"/cancers/extensive-stage-sclc/"},{"id":"limited-stage-sclc","kind":"cancer","name":"Limited-stage small-cell lung cancer","route":"/cancers/limited-stage-sclc/"},{"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/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"}],"technology":[{"id":"organoids","kind":"technology","name":"Patient-derived organoids","route":"/technologies/organoids/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"target":[{"id":"ascl1","kind":"target","name":"ASCL1","route":"/targets/ascl1/"},{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"mycl","kind":"target","name":"MYCL","route":"/targets/mycl/"},{"id":"yap1","kind":"target","name":"YAP1","route":"/targets/yap1/"}],"institution":[{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"term":[{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"histology","kind":"term","name":"Histology","route":"/terms/histology/"}],"person":[{"id":"charles-rudin","kind":"person","name":"Charles M. Rudin","route":"/people/charles-rudin/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"nature-reviews-cancer","kind":"journal","name":"Nature Reviews Cancer","route":"/journals/nature-reviews-cancer/"}],"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/"}],"biomarker":[{"id":"dll3-expression","kind":"biomarker","name":"DLL3 expression","route":"/biomarkers/dll3-expression/"}]}}