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Why many lung cancer patients who have never smoked have worse outcomes

June 13, 2024
University College London
The reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked, has been discovered.

The reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked, has been discovered by researchers from UCL, the Francis Crick Institute and AstraZeneca.

The study, published in Nature Communications, shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it.

In the UK, lung cancer is the third most common type of cancer and the leading cause of cancer death. Around 85% of patients with lung cancer have non-small cell lung cancer (NSCLC), and this is the most common type found in patients who have never smoked. Considered separately, 'never smoked' lung cancer is the fifth most common cause of cancer death in the world.

The most common genetic mutation found in NSCLC is in the epidermal growth factor receptor gene (EGFR), which enables cancer cells to grow faster. It is found in about 10-15% of NSCLC cases in the UK, particularly in patients who have never smoked.

Survival rates vary depending on how advanced the cancer is, with only around a third of patients with Stage IV NSCLC and an EGFR mutation surviving for up to three years.

Lung cancer treatments that target this mutation, known as EGFR inhibitors, have been available for over 15 years. However, while some patients see their cancer tumours shrink with EGFR inhibitors, other patients, particularly those with an additional mutation in the p53 gene (which plays a role in tumour suppression), fail to respond and experience far worse survival rates. But scientists and clinicians have so far been unable to explain why this is the case.

To find the answer, the researchers re-analysed data from trials of the newest EGFR inhibitor, Osimertinib, developed by AstraZeneca. They looked at baseline scans and first follow-up scans taken a few months into treatment for patients with either EGFR-only or with EGFR and p53 mutations.

The team compared every tumour on the scans, far more than were measured in the original trial. They found that for patients with just the EGFR mutations, all tumours got smaller in response to treatment. But for patients with both mutations, while some tumours had shrunk others had grown, providing evidence of rapid drug resistance. This pattern of response, when some but not all areas of a cancer are shrinking in response to a drug treatment within an individual patient, is known as a 'mixed response' and is a challenge for oncologists caring for patients with cancer.

To investigate why some tumours in these patients might be more prone to drug resistance, the team then studied a mouse model with both the EGFR and p53 mutation. They found that within resistant tumours in these mice, far more cancer cells had doubled their genome, giving them extra copies of all their chromosomes.

The researchers then treated lung cancer cells in the lab, some with just the single EGFR mutation and some with both mutations, with an EGFR inhibitor. They found that within five weeks of exposure to the drug, a significantly higher percentage of cells with both the double mutation and double genomes had multiplied into new drug-resistant cells.

Professor Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, said: "We've shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling. This increases the risk of drug-resistant cells developing through chromosomal instability."

Non-small cell lung cancer patients are already tested for EGFR and p53 mutations, but there is currently no standard test to detect the presence of whole genome doubling. The researchers are already looking to develop a diagnostic test for clinical use.

Dr Crispin Hiley, from UCL Cancer Institute and a Consultant Clinical Oncologist at UCLH, said: "Once we can identify patients with both EGFR and p53 mutations whose tumours display whole genome doubling, we can then treat these patients in a more selective way. This might mean more intensive follow up, early radiotherapy or ablation to target resistant tumours, or early use of combinations of EGFR inhibitors, such as Osimertinib, with other drugs including chemotherapy."

This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and Wellcome.

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Materials provided by University College London. Note: Content may be edited for style and length.

Journal Reference:

  1. 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. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nature Communications, 2024; 15 (1) DOI: 10.1038/s41467-024-47606-9

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University College London. "Why many lung cancer patients who have never smoked have worse outcomes." ScienceDaily. ScienceDaily, 13 June 2024. <>.
University College London. (2024, June 13). Why many lung cancer patients who have never smoked have worse outcomes. ScienceDaily. Retrieved July 17, 2024 from
University College London. "Why many lung cancer patients who have never smoked have worse outcomes." ScienceDaily. (accessed July 17, 2024).

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