| Title: |
Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling |
| 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; Lester, JF; Bajaj, A; Nakas, A; Sodha-Ramdeen, A; Tufail, M; Scotland, M; Boyles, R; Rathinam, S; Wilson, C; Marrone, D; Dulloo, S; Fennell, DA; Matharu, G; Shaw, JA; Boleti, E; Cheyne, H; Khalil, M; Richardson, S; Cruickshank, T; Price, G; Kerr, KM; Benafif, S; French, J; Gilbert, K; Naidu, B; Patel, AJ; Osman, A; Enstone, C; Langman, G; Shackleford, H; Djearaman, M; Kadiri, S; Middleton, G; Leek, A; Hodgkinson, JD; Totton, N; Montero, A; Smith, E; Fontaine, E; Granato, F; Paiva-Correia, A; Novasio, J; Rammohan, K; Joseph, L; Bishop, P; Shah, R; Moss, S; Joshi, V; Crosbie, PAJ; Brown, KD; Carter, M; Chaturvedi, A; Oliveira, P; Lindsay, CR; Blackhall, FH; Krebs, MG; Summers, Y; Clipson, A |
| Source: |
Nature Communications , 15 , Article 4871. (2024) |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2024 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
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 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10205078/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10205078/1/Hackshaw_s41467-024-47606-9.pdf; https://discovery.ucl.ac.uk/id/eprint/10205078/ |
| Rights: |
open |
| Accession Number: |
edsbas.6551F867 |
| Database: |
BASE |