{"entity":{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","aka":[],"tldr":"Sequencing 110 small-cell lung cancers found that losing both copies of TP53 and RB1 is obligatory. That is a loss of two brakes, not a gain of a target, which is why the disease has been so hard to drug.","summary":"George, Lim, Jang and colleagues, with Thomas as senior author, sequenced the genomes of 110 small-cell lung cancers. Bi-allelic inactivation of TP53 and RB1 was present in nearly all of them, sometimes through complex genomic rearrangements; two tumours with wild-type RB1 showed chromothripsis producing cyclin D1 overexpression, an alternative route to the same deregulation.\n\nThe paper explains the therapeutic history of the disease. Small-cell lung cancer is defined by the loss of two tumour suppressors, and a loss cannot be inhibited, so forty years of kinase inhibitor development passed it by. The NOTCH finding, inactivating mutations in a quarter of tumours with Notch activation suppressing tumour growth in mouse models, is the one actionable lead the study produced, and it led to DLL3.","asOf":"2026-09-25","links":[{"label":"Nature 2015","url":"https://doi.org/10.1038/nature14664"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26168399/"}],"tags":["lung-evidence"],"related":["paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019","paper-dll3-sclc-clin-cancer-res-2019","paper-ahn-dellphi-301-tarlatamab-sclc-nejm-2023"],"cancers":["lung-cancer","sclc"],"sections":["drug-discovery","diagnostics"],"technologies":["wes-wgs","ngs"],"targets":["tp53","rb1","notch1","dll3"],"drugs":[],"companies":[],"institutions":[],"pathways":["notch","cell-cycle"],"terms":["driver-mutation"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-rare-cancers","b-preclinical-models"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2015,"doi":"10.1038/nature14664","pmid":"26168399","authors":"George J, Lim JS, Jang SJ, et al.","paperType":"basic","findings":["Bi-allelic inactivation of TP53 and RB1 in nearly all 110 tumours, sometimes by complex genomic rearrangements; loss of both is obligatory in small-cell lung cancer.","Two tumours with wild-type RB1 showed chromothripsis leading to overexpression of cyclin D1, an alternative mechanism of Rb1 deregulation.","Somatic genomic rearrangements of TP73 creating an oncogenic TP73 delta exon 2/3 were discovered.","Inactivating mutations in NOTCH family genes in 25 percent of tumours; activating Notch signalling in a mouse model strikingly reduced tumour number and extended survival, and abrogated neuroendocrine gene expression.","Kinase gene mutations were present in rare cases, offering a possible therapeutic opportunity for individual patients."],"whatItMeans":"Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.","caveats":["110 tumours, largely surgical specimens from a disease that is rarely operated on, so the sample is not representative of the extensive-stage majority.","Genomic classification does not map cleanly onto the transcription-factor subtypes proposed four years later.","No treatment has yet been assigned on the basis of a small-cell genome in routine care."],"changedPractice":false,"participants":110},"route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/","neighbours":{"paper":[{"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-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","route":"/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/"},{"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/"}],"cancer":[{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"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":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"term":[{"id":"cell-cycle","kind":"term","name":"Cell cycle","route":"/terms/cell-cycle/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"notch1","kind":"target","name":"NOTCH1","route":"/targets/notch1/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"}],"bottleneck":[{"id":"b-preclinical-models","kind":"bottleneck","name":"Lab models that fail to predict what happens in patients","route":"/bottlenecks/b-preclinical-models/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}],"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/"}],"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/"}]}}