Data from EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors

Abstract

<div>Abstract<p><b>Purpose:</b> Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the <i>EGFR</i> T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study <i>EGFR</i> mutations that confer resistance to this class of agents.</p><p><b>Experimental Design:</b> We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in <i>EGFR</i>-mutant (sensitizing alone or with concurrent <i>EGFR</i> T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant <i>EGFR</i> mutations.</p><p><b>Results:</b> We identified 3 major drug resistance mutations. <i>EGFR</i> L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only <i>EGFR</i> C797S leads to AZD9291 resistance. Cells containing an <i>EGFR</i>-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization.</p><p><b>Conclusions:</b> Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR. <i>Clin Cancer Res; 21(17); 3913–23. ©2015 AACR</i>.</p><p><i>See related commentary by Ayeni et al., p. 3818</i></p></div>