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

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  • 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)

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.

Suggested Citation

  • Celia D. Rouault & Lucile Bansard & Elena Martínez-Balsalobre & Caroline Bonnet & Julien Wicinski & Shuheng Lin & Ludovic Colombeau & Sylvain Debieu & Guillaume Pinna & Marie Vandamme & Margot Machu &, 2025. "Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57476-4
    DOI: 10.1038/s41467-025-57476-4
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