Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
In: Nature communications, Jg. 15 (2024-06-13), Heft 1, S. 4871
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Zugriff:
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.
(© 2024. The Author(s).)
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Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
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Autor/in / Beteiligte Person: | Hobor, S ; Al Bakir, M ; Hiley, CT ; Skrzypski, M ; Frankell, AM ; Bakker, B ; Watkins, TBK ; Markovets, A ; Dry, JR ; Brown, AP ; van der Aart J ; van den Bos H ; Spierings, D ; Oukrif, D ; Novelli, M ; Chakrabarti, T ; Rabinowitz, AH ; Ait Hassou, L ; Litière, S ; Kerr, DL ; Tan, L ; Kelly, G ; Moore, DA ; Renshaw, MJ ; Venkatesan, S ; Hill, W ; Huebner, A ; Martínez-Ruiz, C ; Black, JRM ; Wu, W ; Angelova, M ; McGranahan, N ; Downward, J ; Chmielecki, J ; Barrett, C ; Litchfield, K ; Chew, SK ; Blakely, CM ; de Bruin EC ; Foijer, F ; Vousden, KH ; Bivona, TG ; Hynds, RE ; Kanu, N ; Zaccaria, S ; Grönroos, E ; Swanton, C |
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Zeitschrift: | Nature communications, Jg. 15 (2024-06-13), Heft 1, S. 4871 |
Veröffentlichung: | [London] : Nature Pub. Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2041-1723 (electronic) |
DOI: | 10.1038/s41467-024-47606-9 |
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