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

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.