Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
Nat Commun
; 15(1): 4871, 2024 Jun 13.
Article
in En
| MEDLINE
| ID: mdl-38871738
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tumor Suppressor Protein p53
/
Chromosomal Instability
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ErbB Receptors
/
Lung Neoplasms
/
Mutation
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Commun
Year:
2024
Document type:
Article