| Added by | standudu |
|---|---|
| Group name | EquipeAT |
| Item Type | Journal Article |
| Title | Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3 |
| Creator | Le Clorennec et al. |
| Author | Christophe Le Clorennec |
| Author | Hervé Bazin |
| Author | Olivier Dubreuil |
| Author | Christel Larbouret |
| Author | Charline Ogier |
| Author | Yassamine Lazrek |
| Author | Véronique Garambois |
| Author | Marie-Alix Poul |
| Author | Philippe Mondon |
| Author | Jean-Marc Barret |
| Author | Gérard Mathis |
| Author | Jean-François Prost |
| Author | André Pèlegrin |
| Author | Thierry Chardès |
| Abstract | Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time-resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a nonligand-competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2, and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11-dependent cell-mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody. This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic, A549 lung, and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121. Conversely, both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. Mol Cancer Ther; 16(7); 1312-23. ©2017 AACR. |
| Publication | Molecular Cancer Therapeutics |
| Volume | 16 |
| Issue | 7 |
| Pages | 1312-1323 |
| Date | 07 2017 |
| Journal Abbr | Mol. Cancer Ther. |
| Language | eng |
| DOI | 10.1158/1535-7163.MCT-16-0886 |
| ISSN | 1538-8514 |
| Library Catalog | PubMed |
| Extra | PMID: 28507002 |
| Tags | A549 Cells, Animals, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Murine-Derived, Biomarkers, Tumor, Cell Proliferation, Female, Fluorescence Resonance Energy Transfer, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasms, Neuregulin-1, original, Phosphorylation, Protein Binding, Receptor, ErbB-3, Signal Transduction, Xenograft Model Antitumor Assays |
| Date Added | 2019/05/29 - 16:08:39 |
| Date Modified | 2019/05/29 - 16:08:50 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
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