Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer
Nitin Roper, Anna-Leigh Brown, Jun S Wei, Svetlana Pack, Christopher Trindade, Chul Kim, Olivia Restifo, Shaojian Gao, Sivasish Sindiri, Farid Mehrabadi, Rajaa El Meskini, Zoe Weaver Ohler, Tapan K Maity, Abhilash Venugopalan, Constance M Cultraro, Elizabeth Akoth, Emerson Padiernos, Haobin Chen, Aparna Kesarwala, DeeDee K Smart, Naris Nilubol, Arun Rajan, Zofia Piotrowska, Liqiang Xi, Mark Raffeld, Anna R Panchenko, Cenk Sahinalp, Stephen Hewitt, Chuong D Hoang, Javed Khan, Udayan Guha, Nitin Roper, Anna-Leigh Brown, Jun S Wei, Svetlana Pack, Christopher Trindade, Chul Kim, Olivia Restifo, Shaojian Gao, Sivasish Sindiri, Farid Mehrabadi, Rajaa El Meskini, Zoe Weaver Ohler, Tapan K Maity, Abhilash Venugopalan, Constance M Cultraro, Elizabeth Akoth, Emerson Padiernos, Haobin Chen, Aparna Kesarwala, DeeDee K Smart, Naris Nilubol, Arun Rajan, Zofia Piotrowska, Liqiang Xi, Mark Raffeld, Anna R Panchenko, Cenk Sahinalp, Stephen Hewitt, Chuong D Hoang, Javed Khan, Udayan Guha
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.
Trial registration: ClinicalTrials.gov NCT02759835.
Conflict of interest statement
C.K. receives research funding to his current institution (Georgetown University) from AstraZeneca, Novartis, and Tesaro and received one-time travel support from CARIS Life Science. C.T. owns stock in Gilead, Celgene, Exelixis, Clovis, and Trevena, and he is an employee of the Food and Drug Administration outside of the submitted work. Z.P. has served as a compensated consultant or received honoraria from AstraZeneca, Spectrum, Ariad/Takeda, Novartis, ImmunoGen, AbbVie, GuardantHealth, Genentech, Eli Lilly, InCyte, and Medtronic and receives institutional research funding from Novartis, Takeda, Spectrum, AstraZeneca, and Tesaro. U.G. has a clinical trial agreement (CTA) with AstraZeneca for the current study and receives research funding from AstraZeneca, Esanex, and Aurigene. U.G. is currently an employee of Bristol Myers Squibb. The other authors have no conflicts of interest to report.
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