ArticleNature communications2024
Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33citing papers in PubMed
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Who cites it
33 citing papers in PubMed.
- Osimertinib plus anlotinib in untreated, EGFR-mutated, advanced non-small-cell lung cancer with concurrent alterations: a multicenter phase II study.The oncologist · 2026Trial
- Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations: results from the Phase II BEAVER trial.Nature communications · 2026Trial
- Molecular residual disease analysis of adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer.Nature medicine · 2025Trial
- Aumolertinib with carboplatin-pemetrexed versus aumolertinib for nonsmall cell lung cancer with EGFR and concomitant tumor suppressor genes (ACROSS2): An open-label, multicenter, randomized phase 3 study.CA: a cancer journal for cliniciansTrial
- Observational
- The Role of PD-L1 in Treatment Decision-Making for Perioperative EGFR-Mutated Lung Cancer and its Genomic Analysis.Annals of surgical oncology · 2026Article
- Tetraploids or polyploid giants: who is truly dangerous?Trends in cell biology · 2026Review
- Regulated cell death plasticity in cancer: thresholds, reversibility, and therapeutic failure.Journal of translational medicine · 2026Review
- Single-cell-marker-based subtyping and multi-level analyses uncover the prognostic effects, dysregulations and therapeutic indicative potential of an eight-gene signature in lung adenocarcinoma.Cancer cell international · 2026Article
- Article
- Single and multi-site CT-based radiogenomics analysis of metastatic lung adenocarcinoma and correlations with outcome.European radiology · 2026Article
- Artesunate Induces G0/G1 Phase Arrest in Tumor Cells and Associates With Cyclin-Dependent Kinase 4 (CDK4).Cancer medicine · 2026Article
- Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies.JTO clinical and research reports · 2026Review
- It's a kind of MAGIC: uncovering the origins of chromosomal instability.Signal transduction and targeted therapy · 2026Article
- Distinct p21 dynamics drive alternative routes to whole-genome duplication through a common CDK4/6-dependent polyploid G0 state.bioRxiv : the preprint server for biology · 2026Article
- Deep-Learning Serial CT Prediction of Survival in Immunotherapy-Treated Non-Small Cell Lung Cancer.JAMA network open · 2026Article
- Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following targeted therapy resistance.Frontiers in immunology · 2026Review
- Precision-cut tumor slices: a biomimetic tool for accelerating oncological development from basic research to clinical translation.Frontiers in physiology · 2026Review
- DPEP2 suppresses metastasis via NF-κB-mediated epithelial-mesenchymal transition and M2 polarization in p53-loss non-small cell lung cancer.Cancer cell international · 2025Article
- Revisiting p53 Immunohistochemical Staining and Its Prognostic Implications in Advanced EGFR-Mutated Lung Adenocarcinoma.Cancers · 2025Article
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Authors and funding
48 authors.
Sebastijan Hobor *Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Maise Al Bakir *Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-0846-8332
Crispin T Hiley *Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Marcin Skrzypski *Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Alexander M FrankellCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-0341-7878
Bjorn BakkerCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Thomas B K WatkinsCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Aleksandra MarkovetsOncology Data Science, Oncology R&D, AstraZeneca, Boston, MA, USA.
Jonathan R DryLate Development, Oncology R&D, AstraZeneca, Boston, MA, USA.ORCID 0000-0002-1640-2616
Andrew P BrownLate Development, Oncology R&D, AstraZeneca, Boston, MA, USA.
Jasper van der AartResearch and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK.ORCID 0000-0003-4382-1434
Hilda van den BosEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands.
Diana SpieringsEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands.ORCID 0000-0001-8403-474X
Dahmane OukrifResearch Department of Pathology, University College London Medical School, University Street, London, WC1E 6JJ, UK.
Marco NovelliResearch Department of Pathology, University College London Medical School, University Street, London, WC1E 6JJ, UK.
Turja ChakrabartiDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.
Adam H RabinowitzFurlong Laboratory, EMBL Meyerhofstraße 1, 69117, Heidelberg, Germany.
Laila Ait HassouEuropean Organization for Research and Treatment of Cancer, Brussels, Belgium.
Saskia LitièreBioinformatics & Biostatistics; Francis Crick Institute, London, UK.
D Lucas KerrDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.ORCID 0000-0002-0557-8341
Lisa TanDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.
Gavin KellyBioinformatics & Biostatistics; Francis Crick Institute, London, UK.ORCID 0000-0001-7219-560X
David A MooreCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.ORCID 0000-0002-6296-1312
Matthew J RenshawAdvanced Light Microscopy, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0001-5238-9191
Subramanian VenkatesanCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
William HillCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Ariana HuebnerCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0001-8009-4999
Carlos Martínez-RuizCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.ORCID 0000-0002-4817-0565
James R M BlackCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.ORCID 0000-0001-5598-7752
Wei WuDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.ORCID 0000-0002-6556-067X
Mihaela AngelovaCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-0495-9695
Nicholas McGranahanCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.ORCID 0000-0001-9537-4045
Julian DownwardOncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-2331-4729
Juliann ChmieleckiLate Development, Oncology R&D, AstraZeneca, Boston, MA, USA.
Carl BarrettLate Development, Oncology R&D, AstraZeneca, Boston, MA, USA.
Kevin LitchfieldCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-3725-0914
Su Kit ChewCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Collin M BlakelyDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.ORCID 0000-0001-8134-3651
Elza C de BruinResearch and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK.ORCID 0000-0002-8996-8354
Floris FoijerEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713, the Netherlands.
Karen H Vousdenp53 and Metabolism Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-7365-1766
Trever G BivonaDepartment of Medicine, University of California, San Francisco, CA, 94158, USA.ORCID 0000-0001-5734-4128
TRACERx consortium
Robert E HyndsCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.ORCID 0000-0002-2170-8791
Nnennaya KanuCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK. n.kanu@ucl.ac.uk.
Simone ZaccariaCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK. s.zaccaria@ucl.ac.uk.ORCID 0000-0002-5265-7392
Eva GrönroosCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK. Eva.Gronroos@crick.ac.uk.ORCID 0000-0001-8303-5409
Charles SwantonCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK. Charles.Swanton@crick.ac.uk.ORCID 0000-0002-4299-3018
Funding
Cancer Research UK (CRUK) C11496/A30025Cancer Research UK (CRUK) C416/A21999EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)) 617844EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) 835297Novo Nordisk Fonden (Novo Nordisk Foundation) ID16584Royal Society RSRP\R\210001Wellcome Trust FC001169
Abstract
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
Indexed as
Chromosomal InstabilityErbB ReceptorsLung NeoplasmsMutationTumor Suppressor Protein p53Adenocarcinoma of LungAnimalsCell Line, TumorDNA Copy Number VariationsDrug Resistance, NeoplasmFemaleHumansMaleMiceMolecular Targeted TherapyProtein Kinase InhibitorsEGFR protein, humanErbB ReceptorsProtein Kinase InhibitorsTP53 protein, humanTumor Suppressor Protein p53
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