Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer

[EN]Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistan...

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Autores: Romero Pérez, Inés, Díaz Rodríguez, María Elena, Sánchez Díaz, Laura, Montero González, Juan Carlos, Pandiella Alonso, Atanasio
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Universidad de Salamanca (USAL)
Repositorio:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:dnet:gredos______::32a05c65fbd340d1eba8ce7346a7abbd
Acesso em linha:http://hdl.handle.net/10366/171499
Access Level:acceso abierto
Palavra-chave:Breast cancer
Drug resistance
HER2
Neratinib
Drug Resistance
resistencia a medicamentos
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spelling Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancerRomero Pérez, InésDíaz Rodríguez, María ElenaSánchez Díaz, LauraMontero González, Juan CarlosPandiella Alonso, AtanasioBreast cancerDrug resistanceHER2NeratinibDrug Resistanceresistencia a medicamentos[EN]Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistance. Chronic neratinib exposure of BT474 human HER2+ breast cancer cells resulted in the selection of several clones resistant to the antiproliferative action of the drug. The clones were characterized biochemically and biologically using a variety of techniques. These clones retained HER2 levels similar to parental cells. Knockdown experiments showed that the neratinib-resistant clones retained oncogenic dependence on HER2. Moreover, the tyrosine phosphorylation status of BT474 and the resistant clones was equally sensitive to neratinib. Transcriptomic and Western analyses showed that peptidylarginine deiminase 3 was overexpressed in the three neratinib-resistant clones studied but was undetectable in BT474 cells. Experiments performed in the neratinib-resistant clones showed that reduction of PADI3 or inhibition of its function restored sensitivity to the antiproliferative action of neratinib. Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.Springer Nature202620262024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10366/171499reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésMinistry of Economy and Competitiveness of Spain (BFU2015-71371-R and PID2020-115605RB-I00)Instituto de Salud Carlos III through CIBERONCJunta de Castilla y León (CSI146P20)Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:gredos______::32a05c65fbd340d1eba8ce7346a7abbd2026-06-07T06:28:51Z
dc.title.none.fl_str_mv Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
title Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
spellingShingle Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
Romero Pérez, Inés
Breast cancer
Drug resistance
HER2
Neratinib
Drug Resistance
resistencia a medicamentos
title_short Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
title_full Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
title_fullStr Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
title_full_unstemmed Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
title_sort Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer
dc.creator.none.fl_str_mv Romero Pérez, Inés
Díaz Rodríguez, María Elena
Sánchez Díaz, Laura
Montero González, Juan Carlos
Pandiella Alonso, Atanasio
author Romero Pérez, Inés
author_facet Romero Pérez, Inés
Díaz Rodríguez, María Elena
Sánchez Díaz, Laura
Montero González, Juan Carlos
Pandiella Alonso, Atanasio
author_role author
author2 Díaz Rodríguez, María Elena
Sánchez Díaz, Laura
Montero González, Juan Carlos
Pandiella Alonso, Atanasio
author2_role author
author
author
author
dc.subject.none.fl_str_mv Breast cancer
Drug resistance
HER2
Neratinib
Drug Resistance
resistencia a medicamentos
topic Breast cancer
Drug resistance
HER2
Neratinib
Drug Resistance
resistencia a medicamentos
description [EN]Neratinib is a tyrosine kinase inhibitor that is used for the therapy of patients with HER2+ breast tumors. However, despite its clinical benefit, resistance to the drug may arise. Here we have created cellular models of neratinib resistance to investigate the mechanisms underlying such resistance. Chronic neratinib exposure of BT474 human HER2+ breast cancer cells resulted in the selection of several clones resistant to the antiproliferative action of the drug. The clones were characterized biochemically and biologically using a variety of techniques. These clones retained HER2 levels similar to parental cells. Knockdown experiments showed that the neratinib-resistant clones retained oncogenic dependence on HER2. Moreover, the tyrosine phosphorylation status of BT474 and the resistant clones was equally sensitive to neratinib. Transcriptomic and Western analyses showed that peptidylarginine deiminase 3 was overexpressed in the three neratinib-resistant clones studied but was undetectable in BT474 cells. Experiments performed in the neratinib-resistant clones showed that reduction of PADI3 or inhibition of its function restored sensitivity to the antiproliferative action of neratinib. Moreover, overexpression of FLAG-tagged PADI3 in BT474 cells provoked resistance to the antiproliferative action of neratinib. Together, these results uncover a role of PADI3 in the regulation of sensitivity to neratinib in breast cancer cells overexpressing HER2 and open the possibility of using PADI3 inhibitors to fight resistance to neratinib.
publishDate 2024
dc.date.none.fl_str_mv 2024
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/171499
url http://hdl.handle.net/10366/171499
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R and PID2020-115605RB-I00)
Instituto de Salud Carlos III through CIBERONC
Junta de Castilla y León (CSI146P20)
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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