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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月4日

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  • 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

摘要

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.