# Comprehensive genomic profiles of small cell lung cancer

Source: https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/  
OnCo record `paper-george-sclc-genomic-profiles-nature-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

The 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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Nature
- Year: 2015
- DOI: 10.1038/nature14664
- Authors: George J, Lim JS, Jang SJ, et al.
- 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.
- What it means: 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.

## Sources

- Nature 2015: https://doi.org/10.1038/nature14664
- PubMed: https://pubmed.ncbi.nlm.nih.gov/26168399/
- cBioPortal study sclc_ucologne_2015 (University of Cologne, Nature 2015; 120 small-cell lung cancers, no copy-number profile deposited): https://www.cbioportal.org/study/summary?id=sclc_ucologne_2015

## Connected records

- key papers: [DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer](https://onco.cc/key-papers/paper-dellphi-301-nejm-2023/), [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](https://onco.cc/key-papers/paper-dll3-sclc-clin-cancer-res-2019/), [Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data](https://onco.cc/key-papers/paper-rudin-sclc-molecular-subtypes-nat-rev-cancer-2019/)
- cancers: [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- terms: [Cell cycle](https://onco.cc/terms/cell-cycle/), [Copy number alteration (CNA)](https://onco.cc/terms/copy-number-variation-term/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Somatic mutations from exome and genome sequencing (WXS, WGS)](https://onco.cc/terms/somatic-mutations-wxs-wgs/)
- targets: [CREBBP](https://onco.cc/targets/crebbp/), [DLL3](https://onco.cc/targets/dll3/), [EP300](https://onco.cc/targets/ep300/), [KMT2D](https://onco.cc/targets/kmt2d/), [MYC](https://onco.cc/targets/myc-gene/), [MYCL](https://onco.cc/targets/mycl/), [NOTCH1](https://onco.cc/targets/notch1/), [PTEN](https://onco.cc/targets/pten/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Notch signalling](https://onco.cc/pathways/notch/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [Small cell lung cancer (KEGG map)](https://onco.cc/pathways/sclc-signalling/)
- people: [Roman Thomas](https://onco.cc/people/roman-thomas/)
- bottlenecks: [Lab models that fail to predict what happens in patients](https://onco.cc/bottlenecks/b-preclinical-models/), [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- journals: [Nature](https://onco.cc/journals/nature/)
- 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/)
- ideas: [Run small-cell lung cancer as one platform with shared controls and subtype stratification](https://onco.cc/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/)

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