Dataset Information

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 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 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.

SUBMITTER: Brown BP

PROVIDER: S-EPMC6548651 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Brown Benjamin P BP Zhang Yun-Kai YK Westover David D Yan Yingjun Y Qiao Huan H Huang Vincent V Du Zhenfang Z Smith Jarrod A JA Ross Jeffrey S JS Miller Vincent A VA Ali Siraj S Bazhenova Lyudmila L Schrock Alexa B AB Meiler Jens J Lovly Christine M CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20190222 11

<h4>Purpose</h4>The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with <i>EGFR</i>-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 <i>in vitro</i> screens. Here, we inves ...[more]

PMID: 30796031

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Project description:Background: Although TP53 gain-of-function (GOF) mutations promote cancer survival, its effect on EGFR-TKI efficacy remains unclear. We established EGFR-mutant lung cancer cell lines expressing various TP53 genotypes using CRISPR-Cas9 technology and found that TP53-GOF mutant cells develop an early resistance to EGFR-TKI osimertinib.The goal of this study is to elucidate the mechanisms underlying resistance to osimertinib treatment in TP53 GOF mutations through comprehensive gene analysis using RNA-seq with next-generation sequencing (NGS). Methods: Total RNA was isolated from PC-9 cells overexpressing TP53 R248Q mutation (PC9/p53R248Q: TP53 GOF mutation) and PC-9 cells overexpressing empty vector plasmid (PC9/p53EV: TP53 null) treated with DMSO or osimertinib for 24hours, using the RNeasy Micro Kit , in accordance with the manufacturer’s instructions. RNA samples were quantified by NanoDrop-2000 spectrophotometer, and the quality was confirmed with a 2200 TapeStation. rRNA was removed using MGI Easy rRNA Depletion Kit according to manufacturer's instructions followed by library construction using MGIEasy RNA Directional Library Prep Set (MGI). MGI DNBseq-G400 FAST was used to perform the amplicons deep sequencing following the standard operation protocol. The sequence format was 150bp pair read for all samples. All sequencing reads were trimmed low-quality bases and adapters with Trimmomatic (v.0.38) , and RNA sequencing reads were mapped to hg38 using HISAT2 software . Raw counts for each gene were estimated in each sample using RSEM version 1.3.0 and Bowtie 2. Calculation of the log fold-change (log FC) and p-value were performed using edgeR. Results: We explored the functions of specifically upregulated genes in TP53 GOF mutation after osimertinib treatment by KEGG pathway-enrichment analysis and found that the cytokine-cytokine receptor interaction was the most significantly altered pathway. Hallmark pathway analysis identified the TNF-α/NF-κB pathway was significantly enriched. Furthermore, TRRUST analysis showed enhanced activity of transcription factors especially RELA (p65) and NF-kB1. Conclusions: TP53 GOF mutaion induces osimertinib resistance by activating TNF-α/NF-κB pathway.

Project description:BackgroundStudies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies.Patients and methodsAPOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance.ResultsAPOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis.ConclusionsAPOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Dataset Information

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

Purpose

Results

Conclusions

Publications

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

Similar Datasets

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