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- Title
Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
- Authors
Hobor, Sebastijan; Al Bakir, Maise; Hiley, Crispin T.; Skrzypski, Marcin; Frankell, Alexander M.; Bakker, Bjorn; Watkins, Thomas B. K.; Markovets, Aleksandra; Dry, Jonathan R.; Brown, Andrew P.; van der Aart, Jasper; van den Bos, Hilda; Spierings, Diana; Oukrif, Dahmane; Novelli, Marco; Chakrabarti, Turja; Rabinowitz, Adam H.; Ait Hassou, Laila; Litière, Saskia; Kerr, D. Lucas
- 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. Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.
- Subjects
PROTEIN-tyrosine kinases; EPIDERMAL growth factor receptors; DRUG resistance; CANCER treatment; LABORATORY mice
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-47606-9