Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma

Autores
Santofimia Castaño, Patricia; Lan, Wenjun; Estaras, Matias; Xia, Yi; Cosialls, Emma; Fraunhoffer Navarro, Nicolas Alejandro; Peng, Ling; Chuluyan, Hector Eduardo; Iovanna, Juan
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a "reinforced survival" phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.
Fil: Santofimia Castaño, Patricia. Inserm; Francia
Fil: Lan, Wenjun. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Xia, Yi. Chongqing University; China
Fil: Cosialls, Emma. Inserm; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Peng, Ling. Inserm; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Iovanna, Juan. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina
Materia
ZZW-115
PDAC
NUPR1
DRUG RESISTANCE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/291003
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinomaSantofimia Castaño, PatriciaLan, WenjunEstaras, MatiasXia, YiCosialls, EmmaFraunhoffer Navarro, Nicolas AlejandroPeng, LingChuluyan, Hector EduardoIovanna, JuanZZW-115PDACNUPR1DRUG RESISTANCEhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a "reinforced survival" phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.Fil: Santofimia Castaño, Patricia. Inserm; FranciaFil: Lan, Wenjun. Inserm; FranciaFil: Estaras, Matias. Inserm; FranciaFil: Xia, Yi. Chongqing University; ChinaFil: Cosialls, Emma. Inserm; FranciaFil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Peng, Ling. Inserm; FranciaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Iovanna, Juan. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; ArgentinaNature Publishing Group2025-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/291003Santofimia Castaño, Patricia; Lan, Wenjun; Estaras, Matias; Xia, Yi; Cosialls, Emma; et al.; Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma; Nature Publishing Group; Scientific Reports; 15; 1; 7-2025; 1-152045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-025-11931-winfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-025-11931-winfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T15:42:47Zoai:ri.conicet.gov.ar:11336/291003instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-08-25 15:42:47.855CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
title Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
spellingShingle Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
Santofimia Castaño, Patricia
ZZW-115
PDAC
NUPR1
DRUG RESISTANCE
title_short Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
title_full Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
title_fullStr Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
title_full_unstemmed Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
title_sort Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
dc.creator.none.fl_str_mv Santofimia Castaño, Patricia
Lan, Wenjun
Estaras, Matias
Xia, Yi
Cosialls, Emma
Fraunhoffer Navarro, Nicolas Alejandro
Peng, Ling
Chuluyan, Hector Eduardo
Iovanna, Juan
author Santofimia Castaño, Patricia
author_facet Santofimia Castaño, Patricia
Lan, Wenjun
Estaras, Matias
Xia, Yi
Cosialls, Emma
Fraunhoffer Navarro, Nicolas Alejandro
Peng, Ling
Chuluyan, Hector Eduardo
Iovanna, Juan
author_role author
author2 Lan, Wenjun
Estaras, Matias
Xia, Yi
Cosialls, Emma
Fraunhoffer Navarro, Nicolas Alejandro
Peng, Ling
Chuluyan, Hector Eduardo
Iovanna, Juan
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ZZW-115
PDAC
NUPR1
DRUG RESISTANCE
topic ZZW-115
PDAC
NUPR1
DRUG RESISTANCE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a "reinforced survival" phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.
Fil: Santofimia Castaño, Patricia. Inserm; Francia
Fil: Lan, Wenjun. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Xia, Yi. Chongqing University; China
Fil: Cosialls, Emma. Inserm; Francia
Fil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Peng, Ling. Inserm; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Iovanna, Juan. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche; Argentina
description Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a "reinforced survival" phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.
publishDate 2025
dc.date.none.fl_str_mv 2025-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/291003
Santofimia Castaño, Patricia; Lan, Wenjun; Estaras, Matias; Xia, Yi; Cosialls, Emma; et al.; Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma; Nature Publishing Group; Scientific Reports; 15; 1; 7-2025; 1-15
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/291003
identifier_str_mv Santofimia Castaño, Patricia; Lan, Wenjun; Estaras, Matias; Xia, Yi; Cosialls, Emma; et al.; Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma; Nature Publishing Group; Scientific Reports; 15; 1; 7-2025; 1-15
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-025-11931-w
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-025-11931-w
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.24418

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