Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort
Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-10-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40164-019-0148-7 |
| _version_ | 1828342087219675136 |
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| author | Stephen R. Fairclough Lesli A. Kiedrowski Jessica J. Lin Ori Zelichov Gabi Tarcic Thomas E. Stinchcombe Justin I. Odegaard Richard B. Lanman Alice T. Shaw Rebecca J. Nagy |
| author_facet | Stephen R. Fairclough Lesli A. Kiedrowski Jessica J. Lin Ori Zelichov Gabi Tarcic Thomas E. Stinchcombe Justin I. Odegaard Richard B. Lanman Alice T. Shaw Rebecca J. Nagy |
| author_sort | Stephen R. Fairclough |
| collection | DOAJ |
| description | Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC. |
| first_indexed | 2024-04-13T23:24:32Z |
| format | Article |
| id | doaj.art-a2642d01b2c14be0a9b216a7597b136a |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-04-13T23:24:32Z |
| publishDate | 2019-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-a2642d01b2c14be0a9b216a7597b136a2022-12-22T02:25:07ZengBMCExperimental Hematology & Oncology2162-36192019-10-01811610.1186/s40164-019-0148-7Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohortStephen R. Fairclough0Lesli A. Kiedrowski1Jessica J. Lin2Ori Zelichov3Gabi Tarcic4Thomas E. Stinchcombe5Justin I. Odegaard6Richard B. Lanman7Alice T. Shaw8Rebecca J. Nagy9Guardant Health, Inc.Guardant Health, Inc.Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General HospitalNovellusDx, Jerusalem BioparkNovellusDx, Jerusalem BioparkDuke Cancer InstituteGuardant Health, Inc.Guardant Health, Inc.Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General HospitalGuardant Health, Inc.Abstract Cell-free DNA (cfDNA) next-generation sequencing has the potential to capture tumor heterogeneity and genomic evolution under treatment pressure in a non-invasive manner. Here, we report the detection of EGFR L792 mutations, a non-covalent mechanism of osimertinib resistance, using Guardant360 cfDNA testing in a patient with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) whose disease progressed on osimertinib. We subsequently analyzed a large cohort of over 1800 additional patient samples harboring an EGFR T790M mutation and identified a concomitant L792 mutation in a total of 22 (1.2%) cases. In vitro functional assays demonstrated that the EGFR L858R/T790M/L792F/H mutations conferred intermediate-level resistance to osimertinib. Further understanding of potential acquired resistance mechanisms to targeted therapy may help inform treatment strategy in EGFR-mutant NSCLC.http://link.springer.com/article/10.1186/s40164-019-0148-7Cell-free DNAcfDNAGenomic evolutionAcquired resistanceOsimertinibGuardant360 |
| spellingShingle | Stephen R. Fairclough Lesli A. Kiedrowski Jessica J. Lin Ori Zelichov Gabi Tarcic Thomas E. Stinchcombe Justin I. Odegaard Richard B. Lanman Alice T. Shaw Rebecca J. Nagy Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort Experimental Hematology & Oncology Cell-free DNA cfDNA Genomic evolution Acquired resistance Osimertinib Guardant360 |
| title | Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort |
| title_full | Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort |
| title_fullStr | Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort |
| title_full_unstemmed | Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort |
| title_short | Identification of osimertinib-resistant EGFR L792 mutations by cfDNA sequencing: oncogenic activity assessment and prevalence in large cfDNA cohort |
| title_sort | identification of osimertinib resistant egfr l792 mutations by cfdna sequencing oncogenic activity assessment and prevalence in large cfdna cohort |
| topic | Cell-free DNA cfDNA Genomic evolution Acquired resistance Osimertinib Guardant360 |
| url | http://link.springer.com/article/10.1186/s40164-019-0148-7 |
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