Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors

Sandra Ortiz-Cuaran, Matthias Scheffler, Dennis Plenker, Llona Dahmen, Andreas H. Scheel, Lynnette Fernandez-Cuesta, Lydia Meder, Christine M. Lovly, Thorsten Persigehl, Sabine Merkelbach-Bruse, Marc Bos, Sebastian Michels, Rieke Fischer, Kerstin Albus, Katharina König, Hans Ulrich Schildhaus, Jana Fassunke, Michaela A. Ihle, Helen Pasternack, Carina HeydtChristian Becker, Janine Altmüller, Hongbin Ji, Christian Müller, Alexandra Florin, Johannes M. Heuckmann, Peter Nuernberg, Sascha Ans, Lukas C. Heukamp, Johannes Berg, William Pao, Martin Peifer, Reinhard Buettner, Jürgen Wolf, Roman K. Thomas, Martin L. Sos*

*Corresponding author for this work
123 Citations (Scopus)


Purpose: To identify novel mechanisms of resistance to thirdgeneration EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models. Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS. Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837-47.

Original languageEnglish
JournalClinical Cancer Research
Issue number19
Pages (from-to)4837-4847
Number of pages11
Publication statusPublished - 01.10.2016


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