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

Abstract

Purpose 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. Experimental Design 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. Results 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. Conclusions 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.

Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

“…Based upon experience from other targeted therapy settings (e.g., chronic myeloid leukemia [CML] and EGFR-mutant lung cancer; ref [30][31][32], we hypothesized that sequential ALK inhibitor therapy may predispose patients to develop compound mutations. Indeed, we recently described the development of a compound ALK resistance mutation in a patient treated with crizotinib, ceritinib and lorlatinib (33).…”

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…For example, C797S mutations can occur in cis (on the same allele) or in trans (on a different allele) with T790M [60] or indeed can occur without T790M (loss of T790M mutation) [61]. For those that occur in trans, combination therapy of first-generation EGFR TKIs with third-generation EGFR TKIs may be feasible [62].…”

Circulating DNA in EGFR-mutated lung cancer

“…Despite impressive initial responses, patients eventually develop resistance to these drugs as well, with the acquisition of novel mutations, one of the most common ones being the base substitution, C797S which prevents their binding to the EGFR receptor (43). The context of developing the C797S mutations in relation to other EGFR alleles determines the response to subsequent therapies (44). If the mutation develops in trans-, cells will be sensitive to a combination of first-and third-generation TKIs, whereas mutations in ciswill not respond to EGFR TKIs, alone or in combination.…”