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 (Hospital Dexeus (Barcelona, Catalunya))
Garzón-Ibáñez, M. (Hospital Dexeus (Barcelona, Catalunya))
Bertran-Alamillo, Jordi (Hospital Dexeus (Barcelona, Catalunya))
Jordana-Ariza, Núria (Hospital Dexeus (Barcelona, Catalunya))
Giménez-Capitán, A. (Hospital Dexeus (Barcelona, Catalunya))
García-Peláez, B. (Hospital Dexeus (Barcelona, Catalunya))
Vives-Usano, M. (Hospital Dexeus (Barcelona, Catalunya))
Codony-Servat, Jordi (Hospital Dexeus (Barcelona, Catalunya))
d'Hondt, E. (IN3BIO Europe ltd (Aberdeen, Regne Unit))
Rosell, Rafael (Institut Germans Trias i Pujol)
Molina-Vila, Miguel Ángel (Hospital Dexeus (Barcelona, Catalunya))

Fecha:	2024
Resumen:	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.
Nota:	We thank Isabel Crespo and Sara Ozcoz from the Cytomics Core Facility of the Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for technical assistance. The study was funded by grants from IN3BIO.
Derechos:	Aquest 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.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	EGF ; Vaccine Inhibitors ; Akt ; ERK
Publicado en:	Translational Oncology, Vol. 40 (february 2024) , p. 101878, ISSN 1936-5233

DOI: 10.1016/j.tranon.2024.101878
PMID: 38183801

12 p, 4.1 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Artículos > Artículos de investigación
Artículos > Artículos publicados