Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
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Date
2024-06-13ICR Author
Author
Hobor, S
Al Bakir, M
Hiley, CT
Skrzypski, M
Frankell, AM
Bakker, B
Watkins, TBK
Markovets, A
Dry, JR
Brown, AP
van der Aart, J
van den Bos, H
Spierings, D
Oukrif, D
Novelli, M
Chakrabarti, T
Rabinowitz, AH
Ait Hassou, L
Litière, S
Kerr, DL
Tan, L
Kelly, G
Moore, DA
Renshaw, MJ
Venkatesan, S
Hill, W
Huebner, A
Martínez-Ruiz, C
Black, JRM
Wu, W
Angelova, M
McGranahan, N
Downward, J
Chmielecki, J
Barrett, C
Litchfield, K
Chew, SK
Blakely, CM
de Bruin, EC
Foijer, F
Vousden, KH
Bivona, TG
TRACERx consortium
Hynds, RE
Kanu, N
Zaccaria, S
Grönroos, E
Swanton, C
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Humans
Tumor Suppressor Protein p53
Animals
Chromosomal Instability
Mice
Lung Neoplasms
ErbB Receptors
Mutation
Drug Resistance, Neoplasm
Cell Line, Tumor
Protein Kinase Inhibitors
Adenocarcinoma of Lung
Molecular Targeted Therapy
Female
DNA Copy Number Variations
Male
Research team
Lung Cancer Group
Language
eng
Date accepted
2024-03-28
License start date
2024-06-13
Citation
Nature Communications, 2024, 15 (1), pp. 4871 -
Publisher
Springer Science and Business Media LLC