Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
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期刊论文
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出版模式:
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发表日期:
2024年6月13日
- 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,
- Jason F. Lester,
- Amrita Bajaj,
- Apostolos Nakas,
- Azmina Sodha-Ramdeen,
- Mohamad Tufail,
- Molly Scotland,
- Rebecca Boyles,
- Sridhar Rathinam,
- Claire Wilson,
- Domenic Marrone,
- Sean Dulloo,
- Dean A. Fennell,
- Gurdeep Matharu,
- Jacqui A. Shaw,
- Ekaterini Boleti,
- Heather Cheyne,
- Mohammed Khalil,
- Shirley Richardson,
- Tracey Cruickshank,
- Gillian Price,
- Keith M. Kerr,
- Sarah Benafif,
- Jack French,
- Kayleigh Gilbert,
- Babu Naidu,
- Akshay J. Patel,
- Aya Osman,
- Carol Enstone,
- Gerald Langman,
- Helen Shackleford,
- Madava Djearaman,
- Salma Kadiri,
- Gary Middleton,
- Angela Leek,
- Jack Davies Hodgkinson,
- Nicola Totton,
- Angeles Montero,
- Elaine Smith,
- Eustace Fontaine,
- Felice Granato,
- Antonio Paiva-Correia,
- Juliette Novasio,
- Kendadai Rammohan,
- Leena Joseph,
- Paul Bishop,
- Rajesh Shah,
- Stuart Moss,
- Vijay Joshi,
- Philip A. J. Crosbie,
- Katherine D. Brown,
- Mathew Carter,
- Anshuman Chaturvedi,
- Pedro Oliveira,
- Colin R. Lindsay,
- Fiona H. Blackhall,
- Matthew G. Krebs,
- Yvonne Summers,
- Alexandra Clipson,
- Jonathan Tugwood,
- Alastair Kerr,
- Dominic G. Rothwell,
- Caroline Dive,
- Hugo J. W. L. Aerts,
- Roland F. Schwarz,
- Tom L. Kaufmann,
- Gareth A. Wilson,
- Rachel Rosenthal,
- Peter Van Loo,
- Nicolai J. Birkbak,
- Zoltan Szallasi,
- Judit Kisistok,
- Mateo Sokac,
- Roberto Salgado,
- Miklos Diossy,
- Jonas Demeulemeester,
- Abigail Bunkum,
- Angela Dwornik,
- Alastair Magness,
- Andrew J. Rowan,
- Angeliki Karamani,
- Antonia Toncheva,
- Benny Chain,
- Carla Castignani,
- Chris Bailey,
- Christopher Abbosh,
- Clare Puttick,
- Clare E. Weeden,
- Claudia Lee,
- Corentin Richard,
- Cristina Naceur-Lombardelli,
- David R. Pearce,
- Despoina Karagianni,
- Dhruva Biswas,
- Dina Levi,
- Elizabeth Larose Cadieux,
- Emilia L. Lim,
- Emma Colliver,
- Emma Nye,
- Felip Gálvez-Cancino,
- Francisco Gimeno-Valiente,
- George Kassiotis,
- Georgia Stavrou,
- Gerasimos-Theodoros Mastrokalos,
- Helen L. Lowe,
- Ignacio Garcia Matos,
- Imran Noorani,
- Jacki Goldman,
- James L. Reading,
- Jayant K. Rane,
- Jerome Nicod,
- John A. Hartley,
- Karl S. Peggs,
- Katey S. S. Enfield,
- Kayalvizhi Selvaraju,
- Kerstin Thol,
- Kevin W. Ng,
- Kezhong Chen,
- Krijn Dijkstra,
- Kristiana Grigoriadis,
- Krupa Thakkar,
- Leah Ensell,
- Mansi Shah,
- Maria Litovchenko,
- Mariam Jamal-Hanjani,
- Mariana Werner Sunderland,
- Matthew R. Huska,
- Mark S. Hill,
- Michelle Dietzen,
- Michelle M. Leung,
- Mickael Escudero,
- Miljana Tanić,
- Monica Sivakumar,
- Olga Chervova,
- Olivia Lucas,
- Oriol Pich,
- Othman Al-Sawaf,
- Paulina Prymas,
- Philip Hobson,
- Piotr Pawlik,
- Richard Kevin Stone,
- Robert Bentham,
- Roberto Vendramin,
- Sadegh Saghafinia,
- Samuel Gamble,
- Selvaraju Veeriah,
- Seng Kuong Anakin Ung,
- Sergio A. Quezada,
- Sharon Vanloo,
- Sonya Hessey,
- Sophia Ward,
- Sian Harries,
- Stefan Boeing,
- Stephan Beck,
- Supreet Kaur Bola,
- Takahiro Karasaki,
- Tamara Denner,
- Teresa Marafioti,
- Thomas Patrick Jones,
- Victoria Spanswick,
- Vittorio Barbè,
- Wei-Ting Lu,
- Wing Kin Liu,
- Yin Wu,
- Yutaka Naito,
- Zoe Ramsden,
- Catarina Veiga,
- Gary Royle,
- Charles-Antoine Collins-Fekete,
- Francesco Fraioli,
- Paul Ashford,
- Martin D. Forster,
- Siow Ming Lee,
- Elaine Borg,
- Mary Falzon,
- Dionysis Papadatos-Pastos,
- James Wilson,
- Tanya Ahmad,
- Alexander James Procter,
- Asia Ahmed,
- Magali N. Taylor,
- Arjun Nair,
- David Lawrence,
- Davide Patrini,
- Neal Navani,
- Ricky M. Thakrar,
- Sam M. Janes,
- Emilie Martinoni Hoogenboom,
- Fleur Monk,
- James W. Holding,
- Junaid Choudhary,
- Kunal Bhakhri,
- Marco Scarci,
- Pat Gorman,
- Reena Khiroya,
- Robert C. M. Stephens,
- Yien Ning Sophia Wong,
- Zoltan Kaplar,
- Steve Bandula,
- Allan Hackshaw,
- Anne-Marie Hacker,
- Abigail Sharp,
- Sean Smith,
- Harjot Kaur Dhanda,
- Camilla Pilotti,
- Rachel Leslie,
- Anca Grapa,
- Hanyun Zhang,
- Khalid AbdulJabbar,
- Xiaoxi Pan,
- Yinyin Yuan,
- David Chuter,
- Mairead MacKenzie,
- Serena Chee,
- Aiman Alzetani,
- Judith Cave,
- Jennifer Richards,
- Eric Lim,
- Paulo De Sousa,
- Simon Jordan,
- Alexandra Rice,
- Hilgardt Raubenheimer,
- Harshil Bhayani,
- Lyn Ambrose,
- Anand Devaraj,
- Hema Chavan,
- Sofina Begum,
- Silviu I. Buderi,
- Daniel Kaniu,
- Mpho Malima,
- Sarah Booth,
- Andrew G. Nicholson,
- Nadia Fernandes,
- Pratibha Shah,
- Chiara Proli,
- Madeleine Hewish,
- Sarah Danson,
- Michael J. Shackcloth,
- Lily Robinson,
- Peter Russell,
- Kevin G. Blyth,
- Andrew Kidd,
- Craig Dick,
- John Le Quesne,
- Alan Kirk,
- Mo Asif,
- Rocco Bilancia,
- Nikos Kostoulas,
- Mathew Thomas,
- Robert E. Hynds,
- Nnennaya Kanu,
- Simone Zaccaria,
- Eva Grönroos,
- Charles Swanton
摘要
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.