Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2024-06-13
Date Accepted
2024-03-28
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.
Citation
Nature Communications, 2024, 15 (1), pp. 4871 -
Source Title
Nature Communications
Publisher
Springer Science and Business Media LLC
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Lung Cancer Group