Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer
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.
Authors
- Raphaël Rodriguez (ORCID: https://orcid.org/0000-0001-7668-446X)
- Emmanuelle Charafe‐Jauffret (ORCID: https://orcid.org/0000-0002-0286-1299)
- Lucile Bansard
- Rémy Castellano (ORCID: https://orcid.org/0000-0002-0152-985X)
- Véronique Chevrier (ORCID: https://orcid.org/0000-0001-5692-3398)
- Célia D. Rouault
- Jean‐Marc Pascussi (ORCID: https://orcid.org/0000-0002-5168-5383)
- Christophe Ginestier (ORCID: https://orcid.org/0000-0002-7477-3837)
- Elena Martínez‐Balsalobre (ORCID: https://orcid.org/0000-0003-3287-2228)
- Christophe Lachaud (ORCID: https://orcid.org/0000-0003-2762-1619)
- Cornel Popovici (ORCID: https://orcid.org/0000-0001-8226-3127)
- Géraldine Guasch (ORCID: https://orcid.org/0000-0001-7362-9318)
- Sylvain Debieu
- Olivier Rosnet (ORCID: https://orcid.org/0000-0002-3020-910X)
- Guillaume Pinna (ORCID: https://orcid.org/0000-0001-7841-7250)
- Ludovic Colombeau (ORCID: https://orcid.org/0000-0001-5823-2603)
- Julien Wicinski (ORCID: https://orcid.org/0000-0002-0516-777X)
- Eddy Pasquier (ORCID: https://orcid.org/0000-0003-2824-5002)
- Julie Pannequin (ORCID: https://orcid.org/0000-0002-9956-373X)
- Hagay Sobol
- Shuheng Lin
- Caroline Bonnet (ORCID: https://orcid.org/0000-0001-6931-5121)
- Marie Vandamme
- Margot Machu
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Aix-Marseille Université (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris Sciences et Lettres (FR)
- Institut Pprime (FR)
- La Ligue Contre le Cancer (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Centre de Recherche en Cancérologie de Marseille (FR)
- Institut Paoli-Calmettes (FR)
- Institut de Radiobiologie Cellulaire et Moléculaire (FR)
- Institut de Génomique Fonctionnelle (FR)
- Stabilité Génétique, Cellules Souches et Radiations (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1038/s41467-025-57476-4
- Citations
- 7
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Canceropôle PACA
- Fondation Bettencourt Schueller