Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer

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 () and Christophe Ginestier ()
Additional contact information
Celia D. Rouault: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Lucile Bansard: IGF, University Montpellier, CNRS INSERM
Elena Martínez-Balsalobre: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder Team
Caroline Bonnet: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Julien Wicinski: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Shuheng Lin: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Ludovic Colombeau: Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University
Sylvain Debieu: Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University
Guillaume Pinna: Plateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et Radiations
Marie Vandamme: Plateforme ARN Interférence (PARI), Université Paris Cité, Inserm, CEA Stabilité Génétique Cellules Souches et Radiations
Margot Machu: IGF, University Montpellier, CNRS INSERM
Olivier Rosnet: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Véronique Chevrier: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Cornel Popovici: Aix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-Calmettes
Hagay Sobol: Aix-Marseille University, Cancer Genetic Laboratory, Cancer Biology Department Institut Paoli-Calmettes
Rémy Castellano: CRCM, Aix-Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, TrGET Plateform
Eddy Pasquier: CRCM, INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Reverse Molecular Pharmacology in Pediatric Oncology
Geraldine Guasch: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Raphaël Rodriguez: Institut Curie, CNRS, INSERM, Biomedicine Laboratory PSL Research University
Julie Pannequin: IGF, University Montpellier, CNRS INSERM
Jean-Marc Pascussi: IGF, University Montpellier, CNRS INSERM
Christophe Lachaud: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, DNA Interstrand Crosslink Lesions and Blood Disorder Team
Emmanuelle Charafe-Jauffret: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer
Christophe Ginestier: CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, Epithelial Stem Cells and Cancer Lab, Equipe Labellisée LIGUE Contre Le Cancer

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57476-4

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