Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells
Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S193652332030379X |
| _version_ | 1818381719082893312 |
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| author | Jordi Codony-Servat Silvia García-Roman Miguel Ángel Molina-Vila Jordi Bertran-Alamillo Santiago Viteri Erik d'Hondt Rafael Rosell |
| author_facet | Jordi Codony-Servat Silvia García-Roman Miguel Ángel Molina-Vila Jordi Bertran-Alamillo Santiago Viteri Erik d'Hondt Rafael Rosell |
| author_sort | Jordi Codony-Servat |
| collection | DOAJ |
| description | Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effectively suppressed EGFR downstream pathways in EML4-ALK translocated and CCDC6-RET cells, respectively. In conclusion, anti-EGF VacAbs significantly increased the antitumor activity of TKIs in ALK and RET-positive cell lines. Clinical trials of an EGF vaccine in combination with ALK and RET TKIs are warranted. |
| first_indexed | 2024-12-14T02:39:02Z |
| format | Article |
| id | doaj.art-ffe440135f614a88ae6f23e8d7bf0ef5 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-14T02:39:02Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-ffe440135f614a88ae6f23e8d7bf0ef52022-12-21T23:20:04ZengElsevierTranslational Oncology1936-52332021-01-01141100887Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cellsJordi Codony-Servat0Silvia García-Roman1Miguel Ángel Molina-Vila2Jordi Bertran-Alamillo3Santiago Viteri4Erik d'Hondt5Rafael Rosell6Laboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, Barcelona, SpainLaboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, Barcelona, SpainLaboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, Barcelona, Spain; Corresponding author at: Laboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, C/Sabino Arana 5, 08023 Barcelona, Spain.Laboratory of Oncology/Pangaea Oncology S.L., Quirón-Dexeus University Institute, Barcelona, SpainInstituto Oncológico Dr. Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, SpainIn3Bio (Europe) Ltd, Aberdeen, UKInstituto Oncológico Dr. Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain; Catalan Institute of Oncology, Badalona, Spain; Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, SpainAdvanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effectively suppressed EGFR downstream pathways in EML4-ALK translocated and CCDC6-RET cells, respectively. In conclusion, anti-EGF VacAbs significantly increased the antitumor activity of TKIs in ALK and RET-positive cell lines. Clinical trials of an EGF vaccine in combination with ALK and RET TKIs are warranted.http://www.sciencedirect.com/science/article/pii/S193652332030379X |
| spellingShingle | Jordi Codony-Servat Silvia García-Roman Miguel Ángel Molina-Vila Jordi Bertran-Alamillo Santiago Viteri Erik d'Hondt Rafael Rosell Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells Translational Oncology |
| title | Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells |
| title_full | Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells |
| title_fullStr | Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells |
| title_full_unstemmed | Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells |
| title_short | Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells |
| title_sort | anti epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in alk and ret rearranged lung cancer cells |
| url | http://www.sciencedirect.com/science/article/pii/S193652332030379X |
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