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, Dee Dee K. SmartNaris Nilubol, Arun Rajan, Zofia Piotrowska, Liqiang Xi, Mark Raffeld, Anna R. Panchenko, Cenk Sahinalp, Stephen Hewitt, Chuong D. Hoang, Javed Khan, Udayan Guha

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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.

Original languageEnglish
Article number100007
JournalCell Reports Medicine
Issue number1
StatePublished - Apr 21 2020


  • EGFR mutant lung cancer
  • MET amplification
  • copy number ampplifications
  • neuroendocrine differentiation
  • non-small cell lung cancer
  • osimertinib


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