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

Clin Cancer Res 2015 Sep 11;21(17):3924-33. Epub 2015 May 11.

Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Purpose: A secondary 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 affects the efficacy of subsequent treatments.

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-0560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587765PMC
September 2015
87 Reads

Publication Analysis

Top Keywords

third-generation tkis
16
third-generation egfr
16
resistant third-generation
16
acquired resistance
12
context c797s
12
egfr inhibitors
12
egfr
11
third-generation
10
mutation c797s
8
egfr tkis
8
egfr mutation
8
third-generation tki
8
cells resistant
8
c797s develops
8
resistance third-generation
8
allelic context
8
c797s
7
tkis
6
acquired
6
cells
5

Similar Publications