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Integrative Profiling of T790M Negative EGFR Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities

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Integrative Profiling of T790M Negative EGFR Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Article Type: Research Article Title: Integrative Profiling of T790M Negative EGFR Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities Running Title: Integrative Profiling of Resistance in EGFR Mutated NSCLC Authors: Khi Pin Chua1,16, Yvonne H.F. Teng2,8,16, Aaron C. Tan2,6,16, Angela Takano3, Jacob J.S. Alvarez1, Rahul Nahar1, Neha Rohatgi1, Gillianne G.Y. Lai2, Zaw Win Aung2, Joe P.S. Yeong3, Kiat Hon Lim3, Marjan Mojtabavi Naeini1, Irfahan Kassam1, Amit Jain2, Wan Ling Tan2, Apoorva Gogna4, Chow Wei Too4, Ravindran Kanesvaran2, Quan Sing Ng2, Mei Kim Ang2, Tanujaa Rajasekaran2, Devanand Anantham5, Ghee Chee Phua5, Bien Soo Tan4, Yin Yeng Lee1, Lanying Wang2, Audrey S.M. Teo1, Alexis Jiaying Khng1, Ming Jie Lim1, Lisda Suteja2, Chee Keong Toh2, Wan-Teck Lim2,6,7, N. Gopalakrishna Iyer6,8,9, Wai Leong Tam1,10,11,12, Eng-Huat Tan2, Weiwei Zhai1,13,14, Axel M. Hillmer1,15, Anders J. Skanderup1,17,*, Daniel S.W. Tan1,2,6,8,17,* Affiliations: 1Genome Institute of Singapore, Singapore; 2Division of Medical Oncology, National Cancer Centre Singapore, Singapore; 3Division of Pathology, Singapore General Hospital, Singapore; 4Department of Vascular and Interventional Radiology, Singapore General Hospital, Singapore; 5Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore; 6Duke-NUS Medical School Singapore, Singapore; 7IMCB NCC MPI Singapore Oncogenome Laboratory, Institute of Molecular and Cell Biology, Singapore, Singapore; 8Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore ; 9Division of Surgical Oncology, National Cancer Centre Singapore, Singapore; 10Cancer Science Institute of Singapore, National University of Singapore, Singapore; 11Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 12School of Biological Sciences, Nanyang Technological University, Singapore; 13Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing; 14Center for 1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming; 15Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; 16These authors contributed equally; 17Senior authors Corresponding Authors: Dr Daniel S.W. Tan, 11 Hospital Crescent, National Cancer Centre Singapore, Singapore 169610. Tel: +6564368000; E-mail: [email protected] Dr Anders J. Skanderup, 60 Biopolis St, Genome Institute of Singapore, Singapore 138672. Tel: +6568088000; E-mail: [email protected] Keywords: EGFR mutation, non-small cell lung cancer (NSCLC), oncogenic driver, targeted therapy, tyrosine kinase inhibitor resistance Acknowledgements Funded by grants from the National Medical Research Council (NMRC; Singapore) (NMRC/TCR/007-NCC/2013; NMRC/OFLCG/002-2018; NMRC/OFIRG/0064/2017; OFYIRG16nov013), the NMRC clinician-scientist award (NMRC/CSA/007/2016, D.S.W.T.), the Trailblazer Foundation, Singapore Millennium Foundation, Agency for Science, Research and Technology, Singapore (A*STAR), National Research Foundation (NRF) Fellowship, Singapore (NRF-NRFF2015-04, W.L.T.), and the National Cancer Centre Research Fund, which jointly supported the infrastructure of the Lung Cancer Consortium Singapore. This research is supported in part by Agency for Science, Technology and Research (ASTAR) under its CDAP program (grant no. 1727600057). A.C.T is the recipient of an International Association for the Study of Lung Cancer (IASLC) Fellowship 2018-2020. The computational work for this article was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg). 2 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Disclosure of Potential Conflicts of Interest Aaron C. Tan – Honoraria: Amgen, ThermoFisher. Chee Keong Toh – Consulting or Advisory Role: Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Eisai; Research Funding: Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst), AstraZeneca (Inst). Kiat Hon Lim – Honoraria: AstraZeneca; Consulting or Advisory Role: MSD. Wan Teck Lim – Stock and Other Ownership Interests: Clearbridge Biomedics; Honoraria: Boehringer Ingelheim; Consulting or Advisory Role: Roche, AstraZeneca, MSD Oncology, Novartis, Boehringer Ingelheim; Research Funding: Bristol-Myers Squibb (Inst). Daniel S.W. Tan – Honoraria: Bristol-Myers Squibb, Takeda Pharmaceuticals, Novartis, Roche, Pfizer; Consulting or Advisory Role: Novartis, Merck, Loxo Oncology, AstraZeneca, Roche, Pfizer; Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst). Word Count (Main Text): 5249 Number of Figures: 4 Number of Tables: 0 1 3 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 TRANSLATIONAL RELEVANCE 3 Understanding resistance to targeted therapy requires in depth analysis at multiple levels 4 (single gene, chromosome, transcriptome). Our results illustrate the interplay between 5 genetic alterations, cell lineage plasticity and the tumor microenvironment in shaping 6 divergent TKI resistance and outcome trajectories in EGFR mutated NSCLC. Transcriptomic 7 analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M 8 negative tumors. TP53 alterations, 3q chromosomal amplifications, whole genome doubling 9 and non-aging mutational signatures were also enriched in T790M negative tumors. 10 Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic 11 approaches tailored to a tumor’s adaptive potential. 12 4 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 13 ABSTRACT 14 Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR 15 mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options 16 especially in EGFRT790M negative resistance. 17 Experimental Design: We performed whole exome and transcriptome analysis of 59 first- 18 and second-generation EGFR TKI resistant metastatic EGFR mutated patients to 19 characterize and compare molecular alterations mediating resistance in T790M positive and 20 negative disease. 21 Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene 22 expression in T790M negative tumors, orthogonally validated using multiplex 23 immunohistochemistry. There was enrichment of genomic features such as TP53 alterations, 24 3q chromosomal amplifications, whole genome doubling and non-aging mutational 25 signatures in T790M negative tumors. Almost half of resistant tumors were further classified 26 as Immunehot, with clinical outcomes conditional on immune cell infiltration state and T790M 27 status. Finally, using a Bayesian statistical approach, we explored how T790M negative and 28 positive disease might be predicted using comprehensive genomic and transcriptomic 29 profiles of treatment-naïve patients. 30 Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage 31 plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome 32 trajectories in EGFR mutated NSCLC. Genomic and transcriptomic profiling may facilitate 33 the design of bespoke therapeutic approaches tailored to a tumor’s adaptive potential. 34 35 5 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 14, 2021; DOI: 10.1158/1078-0432.CCR-20-4607 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 36 INTRODUCTION 37 Activating driver mutations in the epidermal growth factor receptor (EGFR) gene 38 represent the most common therapeutically actionable alterations in non-small cell lung 39 cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are standard of care in the first-line 40 setting for advanced or metastatic EGFR mutated NSCLC. The upfront treatment paradigm 41 consists of first-generation (1G; erlotinib, gefitinib), second-generation (2G; afatinib, 42 dacomitinib) or third-generation (3G; osimertinib) EGFR TKI, either alone or in combination 43 with other therapies. However, despite high response rates of up to
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