On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation

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 EGFR-mutant lung cancer. Despite the development of highly selective thirdgeneration 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 in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro 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, whereas cells transduced with L858R/ G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest 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.

Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

“…39 Even though the incidence of this rare mutation upon osimertinib treatment is unknown yet, due to the relatively limited evidence available, it is supposed that G724Smediated resistance preferentially occurs in ex19del but not L858R thus acting in an allele-specific manner. 43 Interestingly, secondgeneration EGFR-TKIs retain kinase affinity in G724S mutants, and afatinib was successful in overcoming G724S-mediated resistance to osimertinib in vitro. 43 Mutations in exon 20 Besides well-known EGFR tertiary mutations ascribed as responsible for osimertinib resistance, other mutations within exon 20 can infrequently occur after progression to osimertinib, but their role in mediating resistance is not established yet.…”

“…43 Interestingly, secondgeneration EGFR-TKIs retain kinase affinity in G724S mutants, and afatinib was successful in overcoming G724S-mediated resistance to osimertinib in vitro. 43 Mutations in exon 20 Besides well-known EGFR tertiary mutations ascribed as responsible for osimertinib resistance, other mutations within exon 20 can infrequently occur after progression to osimertinib, but their role in mediating resistance is not established yet. EGFR S768I constitutes a rare mutation in exon 20 that can be found in conjunction with sensitizing EGFR mutations at the beginning of EGFR-TKI treatment (occurring in <1% cases).…”

“… 39 Even though the incidence of this rare mutation upon osimertinib treatment is unknown yet, due to the relatively limited evidence available, it is supposed that G724S-mediated resistance preferentially occurs in ex19del but not L858R thus acting in an allele-specific manner. 43 Interestingly, second-generation EGFR-TKIs retain kinase affinity in G724S mutants, and afatinib was successful in overcoming G724S-mediated resistance to osimertinib in vitro. 43 …”

Down‐regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle‐related genes

“…5,6 The microarray technology is a high-throughput platform to analyse the gene expression profiling. 5,6 The microarray technology is a high-throughput platform to analyse the gene expression profiling.…”

A CRISPR Test for Rapidly and Sensitively Detecting Circulating EGFR Mutations

“…It has high tissue concordance and significantly faster return of results, and thus, could lead to more complete genotyping of the guideline-recommended biomarkers in more patients [18]. In addition, with the upfront use of osimertinib that is associated with different mechanisms of resistance, detection of T790M mutation becomes less important [19][20][21]. However, the CRISPR-Cas12a system only detects EGFR L858R and T790M.…”