On-target resistance to the mutant-selective EGFR inhibitor osimertinib can develop in an allele specific manner dependent on the original EGFR activating mutation
AUTHORS
- PMID: 30796031 [PubMed].
ABSTRACT
PURPOSE: The third-generation EGFR inhibitor, osimertinib, is the first mutant selective inhibitor that has received regulatory approval for the treatment of patients with -mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in screens. Here, we investigate how G724S confers resistance to osimertinib.
EXPERIMENTAL DESIGN: We combine structure-based predictive modeling of G724S in combination with the two most common EGFR activating mutations, exon 19 deletion (Ex19Del) and L858R, with drug-response models and patient genomic profiling.
RESULTS: Our simulations suggest that the G724S mutation selectively reduces osimertinib binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, while cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggests G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse.
CONCLUSIONS: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the “drug – resistance mutation” pair to one focused on the “activating mutation – drug – resistance mutation” trio. This has broad implications across clinical oncology.