| Added by | mollevi |
|---|---|
| Last modified by | André Pèlegrin |
| Group name | EquipeAP |
| Item Type | Journal Article |
| Title | Neuregulin 1 allosterically enhances the anti-tumor effects of the non-competing anti-HER3 antibody 9F7-F11 by increasing its binding to HER3 |
| Creator | Le Clorennec et al. |
| Author | C. Le Clorennec |
| Author | H. Bazin |
| Author | O. Dubreuil |
| Author | C. Larbouret |
| Author | C. Ogier |
| Author | Y. Lazrek |
| Author | V. Garambois |
| Author | M. A. Poul |
| Author | P. Mondon |
| Author | J. M. Barret |
| Author | G. Mathis |
| Author | J. F. Prost |
| Author | A. Pelegrin |
| Author | T. Chardes |
| 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 non-ligand 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 pre-incubated 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 anti-tumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anti-cancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. |
| Publication | Mol Cancer Ther |
| Volume | 6 |
| Pages | 1312-1323 |
| Date | May 15 2017 |
| Journal Abbr | Mol Cancer Ther |
| DOI | 10.1158/1535-7163.MCT-16-0886 |
| ISSN | 1538-8514 (Electronic) 1535-7163 (Linking) |
| Tags | A549 Cells, Animals, Antibodies, Anti-Idiotypic, Antibodies, Monoclonal, Murine-Derived, Biomarkers, Tumor, Cell Proliferation, Equipe, Female, Fluorescence Resonance Energy Transfer, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasms, Neuregulin-1, original, Phosphorylation, Protein Binding, Receptor, ErbB-3, Signal Transduction, top, Xenograft Model Antitumor Assays |
| Date Added | 2018/07/20 - 10:01:50 |
| Date Modified | 2019/09/12 - 09:46:53 |
| Notes and Attachments | (Note) (Note) 28507002 (Attachment) |
Institut de Recherche en Cancérologie de
