Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
| Title: | Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling |
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| Authors: | Hobor S.; Al Bakir M.; Hiley C. T.; Skrzypski M.; Frankell A. M.; Bakker B.; Watkins T. B. K.; Markovets A.; Dry J. R.; Brown A. P.; van der Aart J.; van den Bos H.; Spierings D.; Oukrif D.; Novelli M.; Chakrabarti T.; Rabinowitz A. H.; Ait Hassou L.; Litiere S.; Kerr D. L.; Tan L.; Kelly G.; Moore D. A.; Renshaw M. J.; Venkatesan S.; Hill W.; Huebner A.; Martinez-Ruiz C.; Black J. R. M.; Wu W.; Angelova M.; McGranahan N.; Downward J.; Chmielecki J.; Barrett C.; Litchfield K.; Chew S. K.; Blakely C. M.; de Bruin E. C.; Foijer F.; Vousden K. H.; Bivona T. G.; Lester J. F.; Bajaj A.; Nakas A.; Sodha-Ramdeen A.; Tufail M.; Scotland M.; Boyles R.; Rathinam S.; Wilson C.; Marrone D.; Dulloo S.; Fennell D. A.; Matharu G.; Shaw J. A.; Boleti E.; Cheyne H.; Khalil M.; Richardson S.; Cruickshank T.; Price G.; Kerr K. M.; Benafif S.; French J.; Gilbert K.; Naidu B.; Patel A. J.; Osman A.; Enstone C.; Langman G.; Shackleford H.; Djearaman M.; Kadiri S.; Middleton G.; Leek A.; Hodgkinson J. D.; 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 P. A. J.; Brown K. D.; Carter M.; Chaturvedi A.; Oliveira P.; Lindsay C. R.; Blackhall F. H.; Krebs M. G.; Summers Y.; Clipson A.; Tugwood J.; Kerr A.; Rothwell D. G.; Dive C.; Aerts H. J. W. L.; Schwarz R. F.; Kaufmann T. L.; Wilson G. A.; Rosenthal R.; Van Loo P.; Birkbak N. J.; Szallasi Z.; Kisistok J.; Sokac M.; Salgado R.; Diossy M.; Demeulemeester J.; Bunkum A.; Dwornik A.; Magness A.; Rowan A. J.; Karamani A.; Toncheva A.; Chain B.; Castignani C.; Bailey C.; Abbosh C.; Puttick C.; Weeden C. E.; Lee C.; Richard C.; Naceur-Lombardelli C.; Pearce D. R.; Karagianni D.; Biswas D.; Levi D.; Larose Cadieux E.; Lim E. L.; Colliver E.; Nye E.; Galvez-Cancino F.; Gimeno-Valiente F.; Kassiotis G.; Stavrou G.; Mastrokalos G. -T.; Lowe H. L.; Matos I. G.; Noorani I.; Goldman J.; Reading J. L.; Rane J. K.; Nicod J.; Hartley J. A.; Peggs K. S.; Enfield K. S. S.; Selvaraju K.; Thol K.; Ng K. W.; Chen K.; Dijkstra K.; Grigoriadis K.; Thakkar K.; Ensell L.; Shah M.; Litovchenko M.; Jamal-Hanjani M.; Werner Sunderland M.; Huska M. R.; Hill M. S.; Dietzen M.; Leung M. M.; Escudero M.; Tanic M.; Sivakumar M.; Chervova O.; Lucas O.; Pich O.; Al-Sawaf O.; Prymas P.; Hobson P.; Pawlik P.; Stone R. K.; Bentham R.; Vendramin R.; Saghafinia S.; Gamble S.; Veeriah S.; Ung S. K. A.; Quezada S. A.; Vanloo S.; Hessey S.; Ward S.; Harries S.; Boeing S.; Beck S.; Bola S. K.; Karasaki T.; Denner T.; Marafioti T.; Jones T. P.; Spanswick V.; Barbe V.; Lu W. -T.; Liu W. K.; Wu Y.; Naito Y.; Ramsden Z.; Veiga C.; Royle G.; Collins-Fekete C. -A.; Fraioli F.; Ashford P.; Forster M. D.; Lee S. M.; Borg E.; Falzon M.; Papadatos-Pastos D.; Wilson J.; Ahmad T.; Procter A. J.; Ahmed A.; Taylor M. N.; Nair A.; Lawrence D.; Patrini D.; Navani N.; Thakrar R. M.; Janes S. M.; Martinoni Hoogenboom E.; Monk F.; Holding J. W.; Choudhary J.; Bhakhri K.; Scarci M.; Gorman P.; Khiroya R.; Stephens R. C. M.; Wong Y. N. S.; Kaplar Z.; Bandula S.; Hackshaw A.; Hacker A. -M.; Sharp A.; Smith S.; Kaur Dhanda H.; Pilotti C.; Leslie R.; Grapa A.; Zhang H.; AbdulJabbar K.; Pan X.; Yuan Y.; Chuter D.; MacKenzie M.; Chee S.; Alzetani A.; Cave J.; Richards J.; Lim E.; De Sousa P.; Jordan S.; Rice A.; Raubenheimer H.; Bhayani H.; Ambrose L.; Devaraj A.; Chavan H.; Begum S.; Buderi S. I.; Kaniu D.; Malima M.; Booth S.; Nicholson A. G.; Fernandes N.; Shah P.; Proli C.; Hewish M.; Danson S.; Shackcloth M. J.; Robinson L.; Russell P.; Blyth K. G.; Kidd A.; Dick C.; Le Quesne J.; Kirk A.; Asif M.; Bilancia R.; Kostoulas N.; Thomas M.; Hynds R. E.; Kanu N.; Zaccaria S.; Gronroos E.; Swanton C. |
| Contributors: | Hobor, S; Al Bakir, M; Hiley, C; Skrzypski, M; Frankell, A; Bakker, B; Watkins, T; Markovets, A; Dry, J; Brown, A; van der Aart, J; van den Bos, H; Spierings, D; Oukrif, D; Novelli, M; Chakrabarti, T; Rabinowitz, A; Ait Hassou, L; Litiere, S; Kerr, D; Tan, L; Kelly, G; Moore, D; Renshaw, M; Venkatesan, S; Hill, W; Huebner, A; Martinez-Ruiz, C; Black, J; Wu, W; Angelova, M; Mcgranahan, N; Downward, J; Chmielecki, J; Barrett, C; Litchfield, K; Chew, S; Blakely, C; de Bruin, E; Foijer, F; Vousden, K; Bivona, T; Lester, J; Bajaj, A; Nakas, A; Sodha-Ramdeen, A; Tufail, M; Scotland, M; Boyles, R; Rathinam, S; Wilson, C; Marrone, D; Dulloo, S; Fennell, D; Matharu, G; Shaw, J; Boleti, E; Cheyne, H; Khalil, M; Richardson, S; Cruickshank, T; Price, G; Kerr, K; Benafif, S; French, J; Gilbert, K; Naidu, B; Patel, A; Osman, A; Enstone, C; Langman, G; Shackleford, H; Djearaman, M; Kadiri, S; Middleton, G; Leek, A; Hodgkinson, J; 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, P; Brown, K; Carter, M; Chaturvedi, A; Oliveira, P; Lindsay, C; Blackhall, F; Krebs, M; Summers, Y; Clipson, A |
| Publisher Information: | Nature Research; GB |
| Publication Year: | 2024 |
| Collection: | Università degli Studi di Milano-Bicocca: BOA (Bicocca Open Archive) |
| Subject Terms: | Adenocarcinoma of Lung; Animal; Cell Line; Tumor; Chromosomal Instability; DNA Copy Number Variation; Drug Resistance; Neoplasm; ErbB Receptor; Female; Human; Lung Neoplasm; Male; Mice; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitor; Tumor Suppressor Protein p53 |
| Description: | The phenomenon of mixed/heterogenous treatment responsesto cancer therapies within an individual patientpresents 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: | ELETTRONICO |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/38871738; info:eu-repo/semantics/altIdentifier/wos/WOS:001457869000001; volume:15; issue:1; journal:NATURE COMMUNICATIONS; https://hdl.handle.net/10281/507720 |
| DOI: | 10.1038/s41467-024-47606-9 |
| Availability: | https://hdl.handle.net/10281/507720; https://doi.org/10.1038/s41467-024-47606-9 |
| Rights: | info:eu-repo/semantics/openAccess ; license:Creative Commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.B2B94FF2 |
| Database: | BASE |