Hobor, S;
Al Bakir, M;
Hiley, CT;
Skrzypski, M;
Frankell, AM;
Bakker, B;
Watkins, TBK;
... Clipson, A; + view all
(2024)
Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
Nature Communications
, 15
, Article 4871. 10.1038/s41467-024-47606-9.
Preview |
Text
Hackshaw_s41467-024-47606-9.pdf Download (3MB) | Preview |
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.
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
