Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
- Author(s)
- 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, DCJ; 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;
- Journal Title
- Nature Communications
- Publication Type
- Research article
- 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.
- Publisher
- Springer Nature
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41467-024-47606-9
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-024-47606-9- Terms of Use/Rights Notice
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Creation Date: 2025-04-24 05:44:26
Last Modified: 2025-04-24 05:45:33