Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways
Background: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies ge...
| Autores: | , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:302196 |
| Acceso en línea: | https://ddd.uab.cat/record/302196 https://dx.doi.org/urn:doi:10.1016/j.tranon.2024.101878 |
| Access Level: | acceso abierto |
| Palabra clave: | EGF Vaccine Inhibitors Akt ERK |
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Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathwaysGarcía-Roman, SílviaGarzón-Ibáñez, M.Bertran-Alamillo, Jordi|||0000-0002-4447-4748Jordana-Ariza, NúriaGiménez-Capitán, A.García Peláez, BeatrizVives-Usano, M.|||0000-0003-0674-6412Codony-Servat, Jordid'Hondt, E.Rosell, Rafael|||0000-0003-0817-3400Molina Vila, Miguel Ángel|||0000-0001-8866-9881EGFVaccine InhibitorsAktERKBackground: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways. Methods: Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used. Anti-EGF VacAbs were obtained by immunizing rabbits with a fusion protein containing a synthetic, highly mutated variant of human EGF. Cell viability was determined by MTT, total and phosphorylated proteins by Western blotting, cell cycle distribution and cell death by flow cytometry and emergence of resistance by microscopic examination in low density cultures. Results: Anti-EGF VacAbs potentiated the antiproliferative effects of MEK, KRAS G12C, BRAF, PI3K and Akt inhibitors in KRAS, NRAS, BRAF and PIK3CA mutant cells and delayed the appearance of resistant clones in vitro. The effects of anti-EGF VacAbs were comparable or superior to those of panitumumab and cetuximab. The combination of anti-EGF VacAbs with the targeted inhibitors effectively suppressed EGFR downstream pathways and sera from patients immunized with an anti-EGF vaccine also blocked activation of EGFR effectors. Conclusions: Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile. 22024-01-0120242024-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/302196https://dx.doi.org/urn:doi:10.1016/j.tranon.2024.101878reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3021962026-06-06T12:50:31Z |
| dc.title.none.fl_str_mv |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| title |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| spellingShingle |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways García-Roman, Sílvia EGF Vaccine Inhibitors Akt ERK |
| title_short |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| title_full |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| title_fullStr |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| title_full_unstemmed |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| title_sort |
Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways |
| dc.creator.none.fl_str_mv |
García-Roman, Sílvia Garzón-Ibáñez, M. Bertran-Alamillo, Jordi|||0000-0002-4447-4748 Jordana-Ariza, Núria Giménez-Capitán, A. García Peláez, Beatriz Vives-Usano, M.|||0000-0003-0674-6412 Codony-Servat, Jordi d'Hondt, E. Rosell, Rafael|||0000-0003-0817-3400 Molina Vila, Miguel Ángel|||0000-0001-8866-9881 |
| author |
García-Roman, Sílvia |
| author_facet |
García-Roman, Sílvia Garzón-Ibáñez, M. Bertran-Alamillo, Jordi|||0000-0002-4447-4748 Jordana-Ariza, Núria Giménez-Capitán, A. García Peláez, Beatriz Vives-Usano, M.|||0000-0003-0674-6412 Codony-Servat, Jordi d'Hondt, E. Rosell, Rafael|||0000-0003-0817-3400 Molina Vila, Miguel Ángel|||0000-0001-8866-9881 |
| author_role |
author |
| author2 |
Garzón-Ibáñez, M. Bertran-Alamillo, Jordi|||0000-0002-4447-4748 Jordana-Ariza, Núria Giménez-Capitán, A. García Peláez, Beatriz Vives-Usano, M.|||0000-0003-0674-6412 Codony-Servat, Jordi d'Hondt, E. Rosell, Rafael|||0000-0003-0817-3400 Molina Vila, Miguel Ángel|||0000-0001-8866-9881 |
| author2_role |
author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
EGF Vaccine Inhibitors Akt ERK |
| topic |
EGF Vaccine Inhibitors Akt ERK |
| description |
Background: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways. Methods: Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used. Anti-EGF VacAbs were obtained by immunizing rabbits with a fusion protein containing a synthetic, highly mutated variant of human EGF. Cell viability was determined by MTT, total and phosphorylated proteins by Western blotting, cell cycle distribution and cell death by flow cytometry and emergence of resistance by microscopic examination in low density cultures. Results: Anti-EGF VacAbs potentiated the antiproliferative effects of MEK, KRAS G12C, BRAF, PI3K and Akt inhibitors in KRAS, NRAS, BRAF and PIK3CA mutant cells and delayed the appearance of resistant clones in vitro. The effects of anti-EGF VacAbs were comparable or superior to those of panitumumab and cetuximab. The combination of anti-EGF VacAbs with the targeted inhibitors effectively suppressed EGFR downstream pathways and sera from patients immunized with an anti-EGF vaccine also blocked activation of EGFR effectors. Conclusions: Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2 2024-01-01 2024 2024-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/302196 https://dx.doi.org/urn:doi:10.1016/j.tranon.2024.101878 |
| url |
https://ddd.uab.cat/record/302196 https://dx.doi.org/urn:doi:10.1016/j.tranon.2024.101878 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
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