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

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posted on 2024-06-14, 10:45 authored by Sebastijan Hobor, Maise Al Bakir, Crispin T Hiley, Marcin Skrzypski, Alexander M Frankell, Bjorn Bakker, Thomas BK 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 RM 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
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.

Funding

Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC2008, Grant title: Van Loo CC2008) Crick (Grant ID: CC2073, Grant title: Vousden CC2073) Crick (Grant ID: CC1119, Grant title: STP Scientific Computing) Crick (Grant ID: CC1069, Grant title: STP Light Microscopy) Crick (Grant ID: CC1062, Grant title: STP Flow Cytometry) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics) Crick (Grant ID: CC1064, Grant title: STP Advanced Sequencing) Crick (Grant ID: CC2088, Grant title: Kassiotis CC2088) Crick (Grant ID: CC2097, Grant title: Downward CC2097) European Research Council (Grant ID: 617844 - THESEUS, Grant title: ERC 617844 - THESEUS) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584)

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