Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer

• Type of Material: Article
• Authors: Nitin Roper, National Institutes of Health; Anna-Leigh Brown, National Institutes of Health; Jun S. Wei, National Institutes of Health; Svetlana Pack, National Institutes of Health; Christopher Trindade, National Institutes of Health; Chul Kim, National Institutes of Health; Olivia Restifo, National Institutes of Health; Shaojian Gao, National Institutes of Health; Sivasish Sindiri, National Institutes of Health; Farid Mehrabadi, National Institutes of Health; Rajaa El Meskini, National Institutes of Health; Zoe Weaver Ohler, National Institutes of Health; Tapan K. Maity, National Institutes of Health; Abhilash Venugopalan, National Institutes of Health; Constance M. Cultraro, National Institutes of Health; Elizabeth Akoth, National Institutes of Health; Emerson Padiernos, National Institutes of Health; Haobin Chen, National Institutes of Health; Aparna Kesarwala, Emory University; DeeDee Smart, National Institutes of Health; Naris Nilubol, National Institutes of Health; Arun Rajan, National Institutes of Health; Zofia Piotrowska, Harvard University; Liqiang Xi, National Institutes of Health; Mark Raffeld, National Institutes of Health; Anna R. Panchenko, National Institutes of Health; Cenk Sahinalp, National Institutes of Health; Stephen Hewitt, National Institutes of Health; Chuong D. Hoang, National Institutes of Health; Javed Khan, National Institutes of Health; Udayan Guha, National Institutes of Health
• Language: English
• Date: 2020-04-21
• Publisher: Cell Press
• Publication Version: Final Published Version
• Copyright Statement: Roper et al., 2020
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.xcrm.2020.100007
• Title of Journal or Parent Work: Cell Reports Medicine
• Volume: 1
• Issue: 1
• Grant/Funding Information: This research was supported by the NIH Intramural Research Program, Center of Cancer Research, and National Cancer Institute and Intramural Research Program of the U.S. National Library of Medicine at the National Institutes of Health.
• Keywords: EGFR mutant lung cancer; osimertinib; copy number ampplifications; MET amplification; non-small cell lung cancer; neuroendocrine differentiation
• Research Categories: Biology, Genetics; Health Sciences, Oncology

Abstract

Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as EGFR C797S. MET amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, PD-L1, KRAS amplification, and ESR1-AKAP12, MKRN1-BRAF fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies.