MZ1 co-operates with trastuzumab in HER2 positive breast cancer

© The Author(s).

Detalles Bibliográficos
Autores: Noblejas-López, María del Mar, Nieto-Jiménez, Cristina, Galán-Moya, Eva María, Tebar-García, David, Pandiella, Atanasio, Burgos, Miguel, Ocaña, Alberto
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/261902
Acceso en línea:http://hdl.handle.net/10261/261902
Access Level:acceso abierto
Palabra clave:HER2+ breast cancer
ERBB2
Trastuzumab
PROTACs
MZ1
id ES_7a1ba3b2b7660ed3bb24ad0a689a8d5b
oai_identifier_str oai:digital.csic.es:10261/261902
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv MZ1 co-operates with trastuzumab in HER2 positive breast cancer
title MZ1 co-operates with trastuzumab in HER2 positive breast cancer
spellingShingle MZ1 co-operates with trastuzumab in HER2 positive breast cancer
Noblejas-López, María del Mar
HER2+ breast cancer
ERBB2
Trastuzumab
PROTACs
MZ1
title_short MZ1 co-operates with trastuzumab in HER2 positive breast cancer
title_full MZ1 co-operates with trastuzumab in HER2 positive breast cancer
title_fullStr MZ1 co-operates with trastuzumab in HER2 positive breast cancer
title_full_unstemmed MZ1 co-operates with trastuzumab in HER2 positive breast cancer
title_sort MZ1 co-operates with trastuzumab in HER2 positive breast cancer
dc.creator.none.fl_str_mv Noblejas-López, María del Mar
Nieto-Jiménez, Cristina
Galán-Moya, Eva María
Tebar-García, David
Pandiella, Atanasio
Burgos, Miguel
Ocaña, Alberto
author Noblejas-López, María del Mar
author_facet Noblejas-López, María del Mar
Nieto-Jiménez, Cristina
Galán-Moya, Eva María
Tebar-García, David
Pandiella, Atanasio
Burgos, Miguel
Ocaña, Alberto
author_role author
author2 Nieto-Jiménez, Cristina
Galán-Moya, Eva María
Tebar-García, David
Pandiella, Atanasio
Burgos, Miguel
Ocaña, Alberto
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Diputación de Albacete
Acepain Albacete
Fundación CRIS contra el Cáncer
Ministerio de Economía y Competitividad (España)
Asociación Española Contra el Cáncer
European Commission
Universidad de Castilla La Mancha
Junta de Comunidades de Castilla-La Mancha
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv HER2+ breast cancer
ERBB2
Trastuzumab
PROTACs
MZ1
topic HER2+ breast cancer
ERBB2
Trastuzumab
PROTACs
MZ1
description © The Author(s).
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/261902
url http://hdl.handle.net/10261/261902
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//BFU2015-71371-R
http://dx.doi.org/10.1186/s13046-021-01907-9
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling MZ1 co-operates with trastuzumab in HER2 positive breast cancerNoblejas-López, María del MarNieto-Jiménez, CristinaGalán-Moya, Eva MaríaTebar-García, DavidPandiella, AtanasioBurgos, MiguelOcaña, AlbertoHER2+ breast cancerERBB2TrastuzumabPROTACsMZ1© The Author(s).[Background]: Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models.[Methods]: BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments.[Results]: MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination.[Conclusions]: We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.This work has been supported by Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña), Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, the scientific foundation of the AECC and the CRIS Foundation (to A. Pandiella). The work carried out in our laboratories receive support from the European Community through the regional development funding program (FEDER). MdM. Noblejas-López was supported by Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). E.M. Galan-Moya is funded by the implementation research program of the UCLM (UCLM resolution date: 31/07/2014), with a contract for accessing the Spanish System of Science, Technology and Innovation-SECTI (co-funded by the European Commission/FSE funds). This work has been supported by Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000173) (to E.M. Galan-Moya and A.Ocana). D. Tébar-García is funded by a contract from Junta de Comunidades de Castilla-La Mancha (SBPLY/19/180501/000173). J.C. Montero is funded by the Instituto de Salud Carlos III through a Miguel Servet program (CPII17/00015) and receives research support from the same institution (PI15/00684 and PI18/00796 M). M. Burgos is funded by Castilla-La Mancha support grant for Biomedicine and Health Science Research ref.: II-2018_11.BioMed CentralInstituto de Salud Carlos IIIDiputación de AlbaceteAcepain AlbaceteFundación CRIS contra el CáncerMinisterio de Economía y Competitividad (España)Asociación Española Contra el CáncerEuropean CommissionUniversidad de Castilla La ManchaJunta de Comunidades de Castilla-La ManchaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/261902reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//BFU2015-71371-Rhttp://dx.doi.org/10.1186/s13046-021-01907-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2619022026-05-22T06:33:51Z
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