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

Authors :
Sebastijan Hobor
Maise Al Bakir
Crispin T. Hiley
Marcin Skrzypski
Alexander M. Frankell
Bjorn Bakker
Thomas B. K. Watkins
Aleksandra Markovets
Jonathan R. Dry
Andrew P. Brown
Jasper van der Aart
Hilda van den Bos
Diana Spierings
Dahmane Oukrif
Marco Novelli
Turja Chakrabarti
Adam H. Rabinowitz
Laila Ait Hassou
Saskia Litière
D. Lucas Kerr
Lisa Tan
Gavin Kelly
David A. Moore
Matthew J. Renshaw
Subramanian Venkatesan
William Hill
Ariana Huebner
Carlos Martínez-Ruiz
James R. M. Black
Wei Wu
Mihaela Angelova
Nicholas McGranahan
Julian Downward
Juliann Chmielecki
Carl Barrett
Kevin Litchfield
Su Kit Chew
Collin M. Blakely
Elza C. de Bruin
Floris Foijer
Karen H. Vousden
Trever G. Bivona
TRACERx consortium
Robert E. Hynds
Nnennaya Kanu
Simone Zaccaria
Eva Grönroos
Charles Swanton
Source :
Nature Communications, Vol 15, Iss 1, Pp 1-21 (2024)
Publication Year :
2024
Publisher :
Nature Portfolio, 2024.

Abstract

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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
15
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.58c4b29e1d8491b8078212067633916
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-024-47606-9