Jun Zhao1, Gen Lin2, Minglei Zhuo1, Zaiwen Fan3, Liyun Miao4, Likun Chen5, Aiping Zeng6, Rong Yin7, Yangming Ou8, Zhihui Shi9, Jie Yin10, Wen Gao11, Jianhua Chen12, Xiangdong Zhou13, Yong Zeng14, Xiang Liu15, Huamin Xu16, Rongrong Chen16, Xuefeng Xia16, David P Carbone17. 1. The First Department of Thoracic Oncology, Beijing University School of Oncology, Beijing Cancer Hospital, Beijing, 100142, China. 2. Department of Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, 350014, China. 3. Department of Medical Oncology, Airforce Medical Center of PLA, Beijing, 100142, China. 4. Department of Respiratory Medicine, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, 210008, China. 5. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China. 6. No. 2 Department of Chemotherapy, Affiliated Tumor Hospital, Guangxi Medical University, Nanning, 530021, China. 7. Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210009, China. 8. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, Department of Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China. 9. Respiratory Medicine Department, the Second Xiangya Hospital of Central South University, Changsha, 410011, China. 10. Department of Respiratory Diseases, Nanjing General Hospital of Nanjing Military Command, Nanjing, 210002, China. 11. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210036, China. 12. Department of Thoracic Medicine, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, China. 13. Department of Respiratory Diseases, The First Affiliated Hospital of Third Military Medical University, Chongqing, 400038, China. 14. Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China. 15. Department of Cardiothoracic Surgery, The Second Hospital Affiliated to University of South China, Hengyang, 421001, China. 16. Geneplus-Beijing Ltd., Floor 9, Building 6, Medical Park Road, Zhongguancun Life Science Park, Beijing, 102206, China. 17. Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, OH, 43210, USA. Electronic address: david.carbone@osumc.edu.
Abstract
OBJECTIVES: The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. MATERIALS AND METHODS: We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes. RESULTS AND CONCLUSION: Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.
OBJECTIVES: The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. MATERIALS AND METHODS: We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes. RESULTS AND CONCLUSION: Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.
Authors: Mariam Jamal-Hanjani; Gareth A Wilson; Nicholas McGranahan; Nicolai J Birkbak; Thomas B K Watkins; Selvaraju Veeriah; Seema Shafi; Diana H Johnson; Richard Mitter; Rachel Rosenthal; Max Salm; Stuart Horswell; Mickael Escudero; Nik Matthews; Andrew Rowan; Tim Chambers; David A Moore; Samra Turajlic; Hang Xu; Siow-Ming Lee; Martin D Forster; Tanya Ahmad; Crispin T Hiley; Christopher Abbosh; Mary Falzon; Elaine Borg; Teresa Marafioti; David Lawrence; Martin Hayward; Shyam Kolvekar; Nikolaos Panagiotopoulos; Sam M Janes; Ricky Thakrar; Asia Ahmed; Fiona Blackhall; Yvonne Summers; Rajesh Shah; Leena Joseph; Anne M Quinn; Phil A Crosbie; Babu Naidu; Gary Middleton; Gerald Langman; Simon Trotter; Marianne Nicolson; Hardy Remmen; Keith Kerr; Mahendran Chetty; Lesley Gomersall; Dean A Fennell; Apostolos Nakas; Sridhar Rathinam; Girija Anand; Sajid Khan; Peter Russell; Veni Ezhil; Babikir Ismail; Melanie Irvin-Sellers; Vineet Prakash; Jason F Lester; Malgorzata Kornaszewska; Richard Attanoos; Haydn Adams; Helen Davies; Stefan Dentro; Philippe Taniere; Brendan O'Sullivan; Helen L Lowe; John A Hartley; Natasha Iles; Harriet Bell; Yenting Ngai; Jacqui A Shaw; Javier Herrero; Zoltan Szallasi; Roland F Schwarz; Aengus Stewart; Sergio A Quezada; John Le Quesne; Peter Van Loo; Caroline Dive; Allan Hackshaw; Charles Swanton Journal: N Engl J Med Date: 2017-04-26 Impact factor: 91.245
Authors: Sai-Hong Ignatius Ou; Jean Cui; Alexa B Schrock; Michael E Goldberg; Viola W Zhu; Lee Albacker; Philip J Stephens; Vincent A Miller; Siraj M Ali Journal: Lung Cancer Date: 2017-04-12 Impact factor: 5.705
Authors: Matthew J Niederst; Lecia V Sequist; John T Poirier; Craig H Mermel; Elizabeth L Lockerman; Angel R Garcia; Ryohei Katayama; Carlotta Costa; Kenneth N Ross; Teresa Moran; Emily Howe; Linnea E Fulton; Hillary E Mulvey; Lindsay A Bernardo; Farhiya Mohamoud; Norikatsu Miyoshi; Paul A VanderLaan; Daniel B Costa; Pasi A Jänne; Darrell R Borger; Sridhar Ramaswamy; Toshi Shioda; Anthony J Iafrate; Gad Getz; Charles M Rudin; Mari Mino-Kenudson; Jeffrey A Engelman Journal: Nat Commun Date: 2015-03-11 Impact factor: 14.919
Authors: D Callegari; K E Ranaghan; C J Woods; R Minari; M Tiseo; M Mor; A J Mulholland; A Lodola Journal: Chem Sci Date: 2018-02-12 Impact factor: 9.825
Authors: Rajeswara Rao Arasada; Konstantin Shilo; Tadaaki Yamada; Jianying Zhang; Seiji Yano; Rashelle Ghanem; Walter Wang; Shinji Takeuchi; Koji Fukuda; Nobuyuki Katakami; Keisuke Tomii; Fumitaka Ogushi; Yasuhiko Nishioka; Tiffany Talabere; Shrilekha Misra; Wenrui Duan; Paolo Fadda; Mohammad A Rahman; Patrick Nana-Sinkam; Jason Evans; Joseph Amann; Elena E Tchekneva; Mikhail M Dikov; David P Carbone Journal: Nat Commun Date: 2018-08-10 Impact factor: 14.919
Authors: Xiuning Le; Sonam Puri; Marcelo V Negrao; Monique B Nilsson; Jacqulyne Robichaux; Theresa Boyle; J Kevin Hicks; Katherine L Lovinger; Emily Roarty; Waree Rinsurongkawong; Ming Tang; Huiying Sun; Yasir Elamin; Lara C Lacerda; Jeff Lewis; Jack A Roth; Stephen G Swisher; J Jack Lee; William N William; Bonnie S Glisson; Jianjun Zhang; Vassiliki A Papadimitrakopoulou; Jhanelle E Gray; John V Heymach Journal: Clin Cancer Res Date: 2018-09-18 Impact factor: 12.531
Authors: Geoffrey R Oxnard; Yuebi Hu; Kathryn F Mileham; Hatim Husain; Daniel B Costa; Philip Tracy; Nora Feeney; Lynette M Sholl; Suzanne E Dahlberg; Amanda J Redig; David J Kwiatkowski; Michael S Rabin; Cloud P Paweletz; Kenneth S Thress; Pasi A Jänne Journal: JAMA Oncol Date: 2018-11-01 Impact factor: 31.777
Authors: Darren A E Cross; Susan E Ashton; Serban Ghiorghiu; Cath Eberlein; Caroline A Nebhan; Paula J Spitzler; Jonathon P Orme; M Raymond V Finlay; Richard A Ward; Martine J Mellor; Gareth Hughes; Amar Rahi; Vivien N Jacobs; Monica Red Brewer; Eiki Ichihara; Jing Sun; Hailing Jin; Peter Ballard; Katherine Al-Kadhimi; Rachel Rowlinson; Teresa Klinowska; Graham H P Richmond; Mireille Cantarini; Dong-Wan Kim; Malcolm R Ranson; William Pao Journal: Cancer Discov Date: 2014-06-03 Impact factor: 39.397
Authors: Collin M Blakely; Thomas B K Watkins; Wei Wu; Beatrice Gini; Jacob J Chabon; Caroline E McCoach; Nicholas McGranahan; Gareth A Wilson; Nicolai J Birkbak; Victor R Olivas; Julia Rotow; Ashley Maynard; Victoria Wang; Matthew A Gubens; Kimberly C Banks; Richard B Lanman; Aleah F Caulin; John St John; Anibal R Cordero; Petros Giannikopoulos; Andrew D Simmons; Philip C Mack; David R Gandara; Hatim Husain; Robert C Doebele; Jonathan W Riess; Maximilian Diehn; Charles Swanton; Trever G Bivona Journal: Nat Genet Date: 2017-11-06 Impact factor: 38.330
Authors: Hailei Du; Lihua Liu; Hongliang Liu; Sheng Luo; Edward F Patz; Carolyn Glass; Li Su; Mulong Du; David C Christiani; Qingyi Wei Journal: Am J Cancer Res Date: 2021-05-15 Impact factor: 6.166
Authors: Chul Kim; Liqiang Xi; Constance M Cultraro; Fang Wei; Gregory Jones; Jordan Cheng; Ahmad Shafiei; Trinh Hoc-Tran Pham; Nitin Roper; Elizabeth Akoth; Azam Ghafoor; Vikram Misra; Nina Monkash; Charles Strom; Michael Tu; Wei Liao; David Chia; Clive Morris; Seth M Steinberg; Hadi Bagheri; David T W Wong; Mark Raffeld; Udayan Guha Journal: Cancers (Basel) Date: 2021-07-03 Impact factor: 6.575