2. Academic Validation
  3. Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors

Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors

  • Cell Chem Biol. 2025 Sep 30:S2451-9456(25)00268-5. doi: 10.1016/j.chembiol.2025.09.003.
Raquel Pequerul 1,  Andrada Constantinescu 2,  Bassam Janji 3,  Akinchan Kumar 3,  Céline Baier 2,  Iris Manosalva 4,  Xavier Parés 5,  Oscar Palacios 6,  Salvatore Spicuglia 4,  Delphine Colignon 7,  Axelle Berrou 8,  Guy Fournet 7,  Paul Berchard 2,  Guillaume Martin 2,  Ismail Ceylan 2,  Rocio Rebollido-Rios 9,  Jaume Farrés 10,  Mileidys Perez-Alea 11
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain; Advanced BioDesign, 69800 Saint Priest, France.
  • 2 Advanced BioDesign, 69800 Saint Priest, France.
  • 3 Department of Cancer Research, Tumor Immunotherapy and Microenvironment (TIME) Group, Luxembourg Institute of Health (LIH), 1210 Luxembourg City, Luxembourg.
  • 4 Aix-Marseille University, INSERM, TAGC, UMR1090, 13266 Marseille, France.
  • 5 Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain.
  • 6 Department of Chemistry, Faculty of Sciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain.
  • 7 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS, Université de Lyon 1, 69622 Lyon, France.
  • 8 CEISAM Laboratory, UMR CNRS 6230, Nantes University, 2 Chemin de la Houssinière, 44322 Nantes, France.
  • 9 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, CECAD Research Center, 50931 Cologne, Germany. Electronic address: rocio.rebollido-rios@uk-koeln.de.
  • 10 Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain. Electronic address: jaume.farres@uab.cat.
  • 11 Advanced BioDesign, 69800 Saint Priest, France. Electronic address: mileidys.perez@a-biodesign.com.
PMID: 41033308 DOI: 10.1016/j.chembiol.2025.09.003
Abstract

Basal-like breast Cancer is an aggressive subtype with limited therapeutic options. Here, transcriptomic analysis of public datasets suggested distinct subtype- and cell-specific expression patterns of ALDH1A isoforms in breast tumors, with ALDH1A3 predominantly expressed in the epithelial cells of basal-like tumors, whereas ALDH1A2 and ALDH1A1 were enriched in stromal and immune-associated subpopulations. High expression of ALDH1A3 and ALDH1A2, but not ALDH1A1, is associated with poor prognosis in high-grade, lymph-node-positive tumors. To evaluate therapeutic targeting, we developed ABD0171, an irreversible, selective ALDH1A3 inhibitor with additional ALDH1A1 activity. ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.

Keywords

ALDH; ALDH1A2; ALDH1A3; TNBC; aldehyde dehydrogenase; breast cancer; bulk and single-cell transcriptomic analysis; chemoresistance; isoform-specific inhibition; prognostic biomarker; triple-negative breast cancer.

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