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. 2016 Oct 1;22(19):4837-4847.
doi: 10.1158/1078-0432.CCR-15-1915. Epub 2016 Jun 1.

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Sandra Ortiz-Cuaran  1 , Matthias Scheffler  2 , Dennis Plenker  3 , Llona Dahmen  1 , Andreas H Scheel  4 , Lynnette Fernandez-Cuesta  5 , Lydia Meder  4 , Christine M Lovly  6 , Thorsten Persigehl  7 , Sabine Merkelbach-Bruse  4 , Marc Bos  1 , Sebastian Michels  2 , Rieke Fischer  2 , Kerstin Albus  4 , Katharina König  8 , Hans-Ulrich Schildhaus  9 , Jana Fassunke  4 , Michaela A Ihle  4 , Helen Pasternack  10 , Carina Heydt  4 , Christian Becker  11 , Janine Altmüller  11 , Hongbin Ji  12 , Christian Müller  1 , Alexandra Florin  4 , Johannes M Heuckmann  13 , Peter Nuernberg  11 , Sascha Ansén  2 , Lukas C Heukamp  14 , Johannes Berg  15 , William Pao  6 , Martin Peifer  16 , Reinhard Buettner  17 , Jürgen Wolf  18 , Roman K Thomas  19 , Martin L Sos  20
Affiliations

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Sandra Ortiz-Cuaran et al. Clin Cancer Res. .

Abstract

Purpose: To identify novel mechanisms of resistance to third-generation 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. ©2016 AACR.

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