1. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
- Author
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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, and Charles Swanton
- Subjects
Science - 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.
- Published
- 2024
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