Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer
Abstract The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identify the antibiotic Nifuroxazide (NIF) as a...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57476-4 |
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| author | Celia D. Rouault Lucile Bansard Elena Martínez-Balsalobre Caroline Bonnet Julien Wicinski Shuheng Lin Ludovic Colombeau Sylvain Debieu Guillaume Pinna Marie Vandamme Margot Machu Olivier Rosnet Véronique Chevrier Cornel Popovici Hagay Sobol Rémy Castellano Eddy Pasquier Geraldine Guasch Raphaël Rodriguez Julie Pannequin Jean-Marc Pascussi Christophe Lachaud Emmanuelle Charafe-Jauffret Christophe Ginestier |
| author_facet | Celia D. Rouault Lucile Bansard Elena Martínez-Balsalobre Caroline Bonnet Julien Wicinski Shuheng Lin Ludovic Colombeau Sylvain Debieu Guillaume Pinna Marie Vandamme Margot Machu Olivier Rosnet Véronique Chevrier Cornel Popovici Hagay Sobol Rémy Castellano Eddy Pasquier Geraldine Guasch Raphaël Rodriguez Julie Pannequin Jean-Marc Pascussi Christophe Lachaud Emmanuelle Charafe-Jauffret Christophe Ginestier |
| author_sort | Celia D. Rouault |
| collection | DOAJ |
| description | Abstract The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identify the antibiotic Nifuroxazide (NIF) as a potent anti-CSC compound. Utilizing a click chemistry strategy, we demonstrate that NIF is a prodrug that is specifically bioactivated in breast CSCs. Mechanistically, NIF-induced CSC death is a result of a synergistic action that combines the generation of DNA interstrand crosslinks with the inhibition of the Fanconi anemia (FA) pathway activity. NIF treatment mimics FA-deficiency through the inhibition of STAT3, which we identify as a non-canonical transcription factor of FA-related genes. NIF induces a chemical HRDness (Homologous Recombination Deficiency) in CSCs that (re)sensitizes breast cancers with innate or acquired resistance to PARP inhibitor (PARPi) in patient-derived xenograft models. Our results suggest that NIF may be useful in combination with PARPi for the treatment of breast tumors, regardless of their HRD status. |
| format | Article |
| id | doaj-art-14279d153b3e48d982cdcbdb8889b986 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-14279d153b3e48d982cdcbdb8889b9862025-08-20T02:47:06ZengNature PortfolioNature Communications2041-17232025-03-0116111910.1038/s41467-025-57476-4Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancerCelia D. Rouault0Lucile Bansard1Elena Martínez-Balsalobre2Caroline Bonnet3Julien Wicinski4Shuheng Lin5Ludovic Colombeau6Sylvain Debieu7Guillaume Pinna8Marie Vandamme9Margot Machu10Olivier Rosnet11Véronique Chevrier12Cornel Popovici13Hagay Sobol14Rémy Castellano15Eddy Pasquier16Geraldine Guasch17Raphaël Rodriguez18Julie Pannequin19Jean-Marc Pascussi20Christophe Lachaud21Emmanuelle Charafe-Jauffret22Christophe Ginestier23CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerIGF, University Montpellier, CNRS INSERMCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder TeamCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerInstitut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research UniversityInstitut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research UniversityPlateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et RadiationsPlateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et RadiationsIGF, University Montpellier, CNRS INSERMCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerAix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-CalmettesAix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-CalmettesCRCM, Aix-Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, TrGET PlateformCRCM, INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Reverse Molecular Pharmacology in Pediatric OncologyCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerInstitut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research UniversityIGF, University Montpellier, CNRS INSERMIGF, University Montpellier, CNRS INSERMCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder TeamCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerCRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le CancerAbstract The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identify the antibiotic Nifuroxazide (NIF) as a potent anti-CSC compound. Utilizing a click chemistry strategy, we demonstrate that NIF is a prodrug that is specifically bioactivated in breast CSCs. Mechanistically, NIF-induced CSC death is a result of a synergistic action that combines the generation of DNA interstrand crosslinks with the inhibition of the Fanconi anemia (FA) pathway activity. NIF treatment mimics FA-deficiency through the inhibition of STAT3, which we identify as a non-canonical transcription factor of FA-related genes. NIF induces a chemical HRDness (Homologous Recombination Deficiency) in CSCs that (re)sensitizes breast cancers with innate or acquired resistance to PARP inhibitor (PARPi) in patient-derived xenograft models. Our results suggest that NIF may be useful in combination with PARPi for the treatment of breast tumors, regardless of their HRD status.https://doi.org/10.1038/s41467-025-57476-4 |
| spellingShingle | Celia D. Rouault Lucile Bansard Elena Martínez-Balsalobre Caroline Bonnet Julien Wicinski Shuheng Lin Ludovic Colombeau Sylvain Debieu Guillaume Pinna Marie Vandamme Margot Machu Olivier Rosnet Véronique Chevrier Cornel Popovici Hagay Sobol Rémy Castellano Eddy Pasquier Geraldine Guasch Raphaël Rodriguez Julie Pannequin Jean-Marc Pascussi Christophe Lachaud Emmanuelle Charafe-Jauffret Christophe Ginestier Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer Nature Communications |
| title | Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer |
| title_full | Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer |
| title_fullStr | Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer |
| title_full_unstemmed | Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer |
| title_short | Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer |
| title_sort | inhibition of the stat3 fanconi anemia axis is synthetic lethal with parp inhibition in breast cancer |
| url | https://doi.org/10.1038/s41467-025-57476-4 |
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