KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma

Autores
Meilerman Abuelafia, Miriam Analia; Santofimia-Castaño, Patricia; Estaras, Matias; Grasso, Daniel Hector; Chuluyan, Hector Eduardo; Lomberk, Gwen; Urrutia, Raul; Dusetti, Nelson Javier; Fraunhoffer Navarro, Nicolas Alejandro; Iovanna, Juan Lucio
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC).Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.ResultsWe observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.
Fil: Meilerman Abuelafia, Miriam Analia. Inserm; Francia
Fil: Santofimia-Castaño, Patricia. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Grasso, Daniel Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina
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: Lomberk, Gwen. Medical College Of Wisconsin; Estados Unidos
Fil: Urrutia, Raul. Medical College Of Wisconsin; Estados Unidos
Fil: Dusetti, Nelson Javier. 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: Iovanna, Juan Lucio. Inserm; Francia
Materia
PDAC
Mutated KRAS
MRTX1133
Gemcitabine
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/291267
Acceder
id CONICETDig_7488411c88ce6e496172c438ffce24fb
oai_identifier_str oai:ri.conicet.gov.ar:11336/291267
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinomaMeilerman Abuelafia, Miriam AnaliaSantofimia-Castaño, PatriciaEstaras, MatiasGrasso, Daniel HectorChuluyan, Hector EduardoLomberk, GwenUrrutia, RaulDusetti, Nelson JavierFraunhoffer Navarro, Nicolas AlejandroIovanna, Juan LucioPDACMutated KRASMRTX1133Gemcitabinehttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC).Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.ResultsWe observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.Fil: Meilerman Abuelafia, Miriam Analia. Inserm; FranciaFil: Santofimia-Castaño, Patricia. Inserm; FranciaFil: Estaras, Matias. Inserm; FranciaFil: Grasso, Daniel Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: 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: Lomberk, Gwen. Medical College Of Wisconsin; Estados UnidosFil: Urrutia, Raul. Medical College Of Wisconsin; Estados UnidosFil: Dusetti, Nelson Javier. 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: Iovanna, Juan Lucio. Inserm; FranciaNeoplasia Press2025-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/291267Meilerman Abuelafia, Miriam Analia; Santofimia-Castaño, Patricia; Estaras, Matias; Grasso, Daniel Hector; Chuluyan, Hector Eduardo; et al.; KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma; Neoplasia Press; Translational Oncology; 57; 5-2025; 1-121936-5233CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S1936523325001524info:eu-repo/semantics/altIdentifier/doi/10.1016/j.tranon.2025.102421info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T15:41:39Zoai:ri.conicet.gov.ar:11336/291267instacron: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 15:41:41.446CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
title KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
spellingShingle KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
Meilerman Abuelafia, Miriam Analia
PDAC
Mutated KRAS
MRTX1133
Gemcitabine
title_short KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
title_full KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
title_fullStr KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
title_full_unstemmed KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
title_sort KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
dc.creator.none.fl_str_mv Meilerman Abuelafia, Miriam Analia
Santofimia-Castaño, Patricia
Estaras, Matias
Grasso, Daniel Hector
Chuluyan, Hector Eduardo
Lomberk, Gwen
Urrutia, Raul
Dusetti, Nelson Javier
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
author Meilerman Abuelafia, Miriam Analia
author_facet Meilerman Abuelafia, Miriam Analia
Santofimia-Castaño, Patricia
Estaras, Matias
Grasso, Daniel Hector
Chuluyan, Hector Eduardo
Lomberk, Gwen
Urrutia, Raul
Dusetti, Nelson Javier
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
author_role author
author2 Santofimia-Castaño, Patricia
Estaras, Matias
Grasso, Daniel Hector
Chuluyan, Hector Eduardo
Lomberk, Gwen
Urrutia, Raul
Dusetti, Nelson Javier
Fraunhoffer Navarro, Nicolas Alejandro
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv PDAC
Mutated KRAS
MRTX1133
Gemcitabine
topic PDAC
Mutated KRAS
MRTX1133
Gemcitabine
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC).Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.ResultsWe observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.
Fil: Meilerman Abuelafia, Miriam Analia. Inserm; Francia
Fil: Santofimia-Castaño, Patricia. Inserm; Francia
Fil: Estaras, Matias. Inserm; Francia
Fil: Grasso, Daniel Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; Argentina
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: Lomberk, Gwen. Medical College Of Wisconsin; Estados Unidos
Fil: Urrutia, Raul. Medical College Of Wisconsin; Estados Unidos
Fil: Dusetti, Nelson Javier. 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: Iovanna, Juan Lucio. Inserm; Francia
description BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC).Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.ResultsWe observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.
publishDate 2025
dc.date.none.fl_str_mv 2025-05
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/11336/291267
Meilerman Abuelafia, Miriam Analia; Santofimia-Castaño, Patricia; Estaras, Matias; Grasso, Daniel Hector; Chuluyan, Hector Eduardo; et al.; KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma; Neoplasia Press; Translational Oncology; 57; 5-2025; 1-12
1936-5233
CONICET Digital
CONICET
url http://hdl.handle.net/11336/291267
identifier_str_mv Meilerman Abuelafia, Miriam Analia; Santofimia-Castaño, Patricia; Estaras, Matias; Grasso, Daniel Hector; Chuluyan, Hector Eduardo; et al.; KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma; Neoplasia Press; Translational Oncology; 57; 5-2025; 1-12
1936-5233
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://linkinghub.elsevier.com/retrieve/pii/S1936523325001524
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.tranon.2025.102421
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Neoplasia Press
publisher.none.fl_str_mv Neoplasia Press
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 13.265058

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