Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer
A significant fraction of non-small cell lung cancer (NSCLC) cases are due to oncogenic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Anti-EGFR antibodies have shown limited clinical benefit for NSCLC, whereas tyrosine kinase inhibitors (TKIs) are effective,...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123002640 |
| _version_ | 1797655122642206720 |
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| author | Brian J. Thomas Caitlyn Guldenpfennig Yue Guan Calvin Winkler Margaret Beecher Michaela Beedy Ashley F. Berendzen Lixin Ma Mark A. Daniels Donald H. Burke David Porciani |
| author_facet | Brian J. Thomas Caitlyn Guldenpfennig Yue Guan Calvin Winkler Margaret Beecher Michaela Beedy Ashley F. Berendzen Lixin Ma Mark A. Daniels Donald H. Burke David Porciani |
| author_sort | Brian J. Thomas |
| collection | DOAJ |
| description | A significant fraction of non-small cell lung cancer (NSCLC) cases are due to oncogenic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Anti-EGFR antibodies have shown limited clinical benefit for NSCLC, whereas tyrosine kinase inhibitors (TKIs) are effective, but resistance ultimately occurs. The current landscape suggests that alternative ligands that target wild-type and mutant EGFRs are desirable for targeted therapy or drug delivery development. Here we evaluate NSCLC targeting using an anti-EGFR aptamer (MinE07). We demonstrate that interaction sites of MinE07 overlap with clinically relevant antibodies targeting extracellular domain III and that MinE07 retains binding to EGFR harboring the most common oncogenic and resistance mutations. When MinE07 was linked to an anti-c-Met aptamer, the EGFR/c-Met bispecific aptamer (bsApt) showed superior labeling of NSCLC cells in vitro relative to monospecific aptamers. However, dual targeting in vivo did not improve the recognition of NSCLC xenografts compared to MinE07. Interestingly, biodistribution of Cy7-labeled bsApt differed significantly from Alexa Fluor 750-labeled bsApt. Overall, our findings demonstrate that aptamer formulations containing MinE07 can target ectopic lung cancer without additional stabilization or PEGylation and highlights the potential of MinE07 as a targeting reagent for the recognition of NSCLC harboring clinically relevant EGFRs. |
| first_indexed | 2024-03-11T17:09:34Z |
| format | Article |
| id | doaj.art-a21d444d7c774c959bf15916e11144f4 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-11T17:09:34Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-a21d444d7c774c959bf15916e11144f42023-10-20T06:39:13ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-12-0134102046Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamerBrian J. Thomas0Caitlyn Guldenpfennig1Yue Guan2Calvin Winkler3Margaret Beecher4Michaela Beedy5Ashley F. Berendzen6Lixin Ma7Mark A. Daniels8Donald H. Burke9David Porciani10Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USADepartment of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USADepartment of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USADepartment of Biological Sciences, University of Missouri, Columbia, MO 65211, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Biochemistry, Westminster College, Fulton, MO 65251, USAResearch Division/Biomolecular Imaging Center, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USAResearch Division/Biomolecular Imaging Center, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA; Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65212, USADepartment of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USADepartment of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA; Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA; Corresponding author: Donald H. Burke, Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA.Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA; Corresponding author: David Porciani, Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA.A significant fraction of non-small cell lung cancer (NSCLC) cases are due to oncogenic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Anti-EGFR antibodies have shown limited clinical benefit for NSCLC, whereas tyrosine kinase inhibitors (TKIs) are effective, but resistance ultimately occurs. The current landscape suggests that alternative ligands that target wild-type and mutant EGFRs are desirable for targeted therapy or drug delivery development. Here we evaluate NSCLC targeting using an anti-EGFR aptamer (MinE07). We demonstrate that interaction sites of MinE07 overlap with clinically relevant antibodies targeting extracellular domain III and that MinE07 retains binding to EGFR harboring the most common oncogenic and resistance mutations. When MinE07 was linked to an anti-c-Met aptamer, the EGFR/c-Met bispecific aptamer (bsApt) showed superior labeling of NSCLC cells in vitro relative to monospecific aptamers. However, dual targeting in vivo did not improve the recognition of NSCLC xenografts compared to MinE07. Interestingly, biodistribution of Cy7-labeled bsApt differed significantly from Alexa Fluor 750-labeled bsApt. Overall, our findings demonstrate that aptamer formulations containing MinE07 can target ectopic lung cancer without additional stabilization or PEGylation and highlights the potential of MinE07 as a targeting reagent for the recognition of NSCLC harboring clinically relevant EGFRs.http://www.sciencedirect.com/science/article/pii/S2162253123002640MT: Delivery Strategiesaptamersnon-small cell lung canceroligonucleotidestumor cell-surface receptorsmolecular engineering |
| spellingShingle | Brian J. Thomas Caitlyn Guldenpfennig Yue Guan Calvin Winkler Margaret Beecher Michaela Beedy Ashley F. Berendzen Lixin Ma Mark A. Daniels Donald H. Burke David Porciani Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer Molecular Therapy: Nucleic Acids MT: Delivery Strategies aptamers non-small cell lung cancer oligonucleotides tumor cell-surface receptors molecular engineering |
| title | Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer |
| title_full | Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer |
| title_fullStr | Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer |
| title_full_unstemmed | Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer |
| title_short | Targeting lung cancer with clinically relevant EGFR mutations using anti-EGFR RNA aptamer |
| title_sort | targeting lung cancer with clinically relevant egfr mutations using anti egfr rna aptamer |
| topic | MT: Delivery Strategies aptamers non-small cell lung cancer oligonucleotides tumor cell-surface receptors molecular engineering |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123002640 |
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