dc.contributor.author | Hobor, S | |
dc.contributor.author | Al Bakir, M | |
dc.contributor.author | Hiley, CT | |
dc.contributor.author | Skrzypski, M | |
dc.contributor.author | Frankell, AM | |
dc.contributor.author | Bakker, B | |
dc.contributor.author | Watkins, TBK | |
dc.contributor.author | Markovets, A | |
dc.contributor.author | Dry, JR | |
dc.contributor.author | Brown, AP | |
dc.contributor.author | van der Aart, J | |
dc.contributor.author | van den Bos, H | |
dc.contributor.author | Spierings, D | |
dc.contributor.author | Oukrif, D | |
dc.contributor.author | Novelli, M | |
dc.contributor.author | Chakrabarti, T | |
dc.contributor.author | Rabinowitz, AH | |
dc.contributor.author | Ait Hassou, L | |
dc.contributor.author | Litière, S | |
dc.contributor.author | Kerr, DL | |
dc.contributor.author | Tan, L | |
dc.contributor.author | Kelly, G | |
dc.contributor.author | Moore, DA | |
dc.contributor.author | Renshaw, MJ | |
dc.contributor.author | Venkatesan, S | |
dc.contributor.author | Hill, W | |
dc.contributor.author | Huebner, A | |
dc.contributor.author | Martínez-Ruiz, C | |
dc.contributor.author | Black, JRM | |
dc.contributor.author | Wu, W | |
dc.contributor.author | Angelova, M | |
dc.contributor.author | McGranahan, N | |
dc.contributor.author | Downward, J | |
dc.contributor.author | Chmielecki, J | |
dc.contributor.author | Barrett, C | |
dc.contributor.author | Litchfield, K | |
dc.contributor.author | Chew, SK | |
dc.contributor.author | Blakely, CM | |
dc.contributor.author | de Bruin, EC | |
dc.contributor.author | Foijer, F | |
dc.contributor.author | Vousden, KH | |
dc.contributor.author | Bivona, TG | |
dc.contributor.author | TRACERx consortium | |
dc.contributor.author | Hynds, RE | |
dc.contributor.author | Kanu, N | |
dc.contributor.author | Zaccaria, S | |
dc.contributor.author | Grönroos, E | |
dc.contributor.author | Swanton, C | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-09-06T10:42:50Z | |
dc.date.available | 2024-09-06T10:42:50Z | |
dc.date.issued | 2024-06-13 | |
dc.identifier | 4871 | |
dc.identifier | 10.1038/s41467-024-47606-9 | |
dc.identifier.citation | Nature Communications, 2024, 15 (1), pp. 4871 - | en_US |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6383 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-024-47606-9 | |
dc.identifier.doi | 10.1038/s41467-024-47606-9 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 4871 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | Springer Science and Business Media LLC | en_US |
dc.relation.ispartof | Nature Communications | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.subject | Animals | |
dc.subject | Chromosomal Instability | |
dc.subject | Mice | |
dc.subject | Lung Neoplasms | |
dc.subject | ErbB Receptors | |
dc.subject | Mutation | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Cell Line, Tumor | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Adenocarcinoma of Lung | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Female | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Male | |
dc.title | Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-03-28 | |
dc.date.updated | 2024-09-06T10:42:14Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41467-024-47606-9 | en_US |
rioxxterms.licenseref.startdate | 2024-06-13 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38871738 | |
pubs.issue | 1 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Closed research teams/Lung Cancer Group | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41467-024-47606-9 | |
pubs.volume | 15 | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |
icr.provenance | Deposited by Mr Arek Surman on 2024-09-06. Deposit type is initial. No. of files: 1. Files: s41467-024-47606-9.pdf | |