KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma
Background: Emerging 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 of...
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Elsevier
2025-07-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001524 |
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| author | Analia Meilerman Abuelafia Patricia Santofimia-Castaño Matias Estaras Daniel Grasso Eduardo Chuluyan Gwen Lomberk Raul Urrutia Nelson Dusetti Nicolas Fraunhoffer Juan Iovanna |
| author_facet | Analia Meilerman Abuelafia Patricia Santofimia-Castaño Matias Estaras Daniel Grasso Eduardo Chuluyan Gwen Lomberk Raul Urrutia Nelson Dusetti Nicolas Fraunhoffer Juan Iovanna |
| author_sort | Analia Meilerman Abuelafia |
| collection | DOAJ |
| description | Background: Emerging 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 Design: Three 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. Results: We 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. Conclusions: This dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer. |
| format | Article |
| id | doaj-art-450cf8be9fb84d9a92c2e3471e4dea07 |
| institution | OA Journals |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-450cf8be9fb84d9a92c2e3471e4dea072025-08-20T02:26:10ZengElsevierTranslational Oncology1936-52332025-07-015710242110.1016/j.tranon.2025.102421KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinomaAnalia Meilerman Abuelafia0Patricia Santofimia-Castaño1Matias Estaras2Daniel Grasso3Eduardo Chuluyan4Gwen Lomberk5Raul Urrutia6Nelson Dusetti7Nicolas Fraunhoffer8Juan Iovanna9Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, France; Programa franco-argentino de estudio del Cáncer de Páncreas, ArgentinaCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, France; Programa franco-argentino de estudio del Cáncer de Páncreas, ArgentinaCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, FrancePrograma franco-argentino de estudio del Cáncer de Páncreas, Argentina; Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina; Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, ArgentinaPrograma franco-argentino de estudio del Cáncer de Páncreas, Argentina; Buenos Aires University, Center for Pharmacological and Botanical Studies, Faculty of Medicine, National Council for Scientific and Technical Research, Buenos Aires C1121ABG, Argentina; Buenos Aires University, Faculty of Medicine, Department of Microbiology, Parasitology and Immunology, Buenos Aires C1121ABG, ArgentinaDivision of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USAGenomic Science and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USACentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, France; Programa franco-argentino de estudio del Cáncer de Páncreas, ArgentinaCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, France; Programa franco-argentino de estudio del Cáncer de Páncreas, Argentina; Buenos Aires University, Center for Pharmacological and Botanical Studies, Faculty of Medicine, National Council for Scientific and Technical Research, Buenos Aires C1121ABG, Argentina; Co-Correspondence author at. Centre de Recherche en Cancérologie de Marseille, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France.Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, Equipe labélisée Ligue Nationale contre le cancer, France; Programa franco-argentino de estudio del Cáncer de Páncreas, Argentina; Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina; University Arturo Jauretche, Florencio Varela, Buenos Aires, Argentina; Co-Correspondence author at. Centre de Recherche en Cancérologie de Marseille, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France.Background: Emerging 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 Design: Three 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. Results: We 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. Conclusions: This dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.http://www.sciencedirect.com/science/article/pii/S1936523325001524PDACSenescence-likeMutated KRASMRTX1133GemcitabineResistance |
| spellingShingle | Analia Meilerman Abuelafia Patricia Santofimia-Castaño Matias Estaras Daniel Grasso Eduardo Chuluyan Gwen Lomberk Raul Urrutia Nelson Dusetti Nicolas Fraunhoffer Juan Iovanna KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma Translational Oncology PDAC Senescence-like Mutated KRAS MRTX1133 Gemcitabine Resistance |
| title | 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_short | 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 |
| topic | PDAC Senescence-like Mutated KRAS MRTX1133 Gemcitabine Resistance |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001524 |
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