Hobor, S., Al Bakir, M. orcid.org/0000-0002-0846-8332, Hiley, C.T. et al. (292 more authors) (2024) Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nature Communications, 15. 4871. ISSN 2041-1723
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 <jats:italic>EGFR</jats:italic> and <jats:italic>TP53</jats:italic>, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an <jats:italic>EGFR</jats:italic> mutation alone. The combined presence of whole genome doubling (WGD) and <jats:italic>TP53</jats:italic> 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 <jats:italic>p53</jats:italic>-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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Humans; Tumor Suppressor Protein p53; Animals; Chromosomal Instability; Mice; Lung Neoplasms; ErbB Receptors; Mutation; Drug Resistance, Neoplasm; Cell Line, Tumor; Protein Kinase Inhibitors; Adenocarcinoma of Lung; Molecular Targeted Therapy; Female; DNA Copy Number Variations; Male |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Jan 2025 16:02 |
Last Modified: | 28 Jan 2025 16:02 |
Published Version: | https://doi.org/10.1038/s41467-024-47606-9 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-024-47606-9 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:222505 |