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Publication : Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

First Author	Hobor S	Year	2024
Journal	Nat Commun	Volume	15
Issue	1	Pages	4871
PubMed ID	38871738	Mgi Jnum	J:349880
Mgi Id	MGI:7659956	Doi	10.1038/s41467-024-47606-9
Citation	Hobor S, et al. (2024) Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nat Commun 15(1):4871

abstractText

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.

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Publication : Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

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