Abstract
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). 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. 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.
Highlights
In EGFR-mutant lung adenocarcinoma, targeted therapy with EGFR tyrosine kinase inhibitors (TKI) performs substantially better than standard chemotherapy in terms of response rate (RR), progression-free survival (PFS), and tolerability [1]
Mechanisms of primary and acquired resistance to thirdgeneration EGFR inhibitors We obtained specimens from seven patients treated with thirdgeneration EGFR inhibitors AZD9291 (n 1⁄4 5) or rociletinib (n 1⁄4 2), within two clinical trials after acquired EGFRT790M-positive resistance to first- or second-generation EGFR kinase inhibitors
The pattern of response varied across these patients: two patients (P1 and P3) experienced primary resistance to rociletinib, whereas two patients had stable disease (P2 and P4) under treatment with AZD9291
Summary
In EGFR-mutant lung adenocarcinoma, targeted therapy with EGFR tyrosine kinase inhibitors (TKI) performs substantially better than standard chemotherapy in terms of response rate (RR), progression-free survival (PFS), and tolerability [1]. A third generation of covalent EGFR TKIs that target EGFR T790M as well as the activating EGFR mutations (e.g., L858R or exon 19 deletion), Oncology Cologne–Bonn, Medical Faculty, University of Cologne, Cologne, Germany. Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
