The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies

Matthew J. Niederst, Haichuan Hu, Hillary E. Mulvey, Elizabeth L. Lockerman, Angel R. Garcia, Zofia Piotrowska, Lecia V. Sequist, Jeffrey A. Engelman

A secondary epidermal growth factor receptor (EGFR) mutation, T790M, is the most common resistance mechanism in EGFR mutant adenocarcinomas that have progressed on erlotinib. Third generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described. To study acquired resistance to third generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third generation TKI and then characterized using cell and molecular analyses. Cells resistant to a third generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third generation EGFR TKIs, but will be sensitive to a combination of first and third generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild type for T790 (when third generation TKIs are administered in the first line setting), the cells are resistant to third generation TKIs, but retain sensitivity to first generation TKIs. Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles impacts the efficacy of subsequent treatments.