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

Abstract

<div>Abstract<p><b>Purpose:</b> 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).</p><p><b>Experimental Design:</b> 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 <i>in vitro</i> models.</p><p><b>Results:</b> We found recurrent amplification of either <i>MET</i> or <i>ERBB2</i> 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 <i>KRAS</i><sup>G12S</sup> 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 <i>EGFR</i>-mutant cells expressing mutant <i>KRAS</i>.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(19); 4837–47. ©2016 AACR</i>.</p></div>