Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma
Abstract 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 inhib...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-11931-w |
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| author | Patricia Santofimia-Castaño Wenjun Lan Matias Estaras Yi Xia Emma Cosialls Nicolas Fraunhoffer Ling Peng Eduardo Chuluyan Juan Iovanna |
| author_facet | Patricia Santofimia-Castaño Wenjun Lan Matias Estaras Yi Xia Emma Cosialls Nicolas Fraunhoffer Ling Peng Eduardo Chuluyan Juan Iovanna |
| author_sort | Patricia Santofimia-Castaño |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
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| series | Scientific Reports |
| spelling | doaj-art-672700396f70460bb236b0bafee82d2f2025-08-20T03:46:01ZengNature PortfolioScientific Reports2045-23222025-07-0115111510.1038/s41598-025-11931-wMechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinomaPatricia Santofimia-Castaño0Wenjun Lan1Matias Estaras2Yi Xia3Emma Cosialls4Nicolas Fraunhoffer5Ling Peng6Eduardo Chuluyan7Juan Iovanna8Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyChongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing UniversityCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyAix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyCentro de Estudios Farmacológicos y Botánicos (CEFYBO)-Facultad de Medicina UBA-CONICET, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y TécnicasCentre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, « Equipe Labellisée Ligue Contre le Cancer », Parc Scientifique et Technologique de LuminyAbstract 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.https://doi.org/10.1038/s41598-025-11931-w |
| spellingShingle | Patricia Santofimia-Castaño Wenjun Lan Matias Estaras Yi Xia Emma Cosialls Nicolas Fraunhoffer Ling Peng Eduardo Chuluyan Juan Iovanna Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-025-11931-w |
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