A vitamin D-based strategy overcomes chemoresistance in prostate cancer

  • Br J Pharmacol. 2024 Jul 9. doi: 10.1111/bph.16492.
Kateryna Len-Tayon  1  2  3  4 ,  Claire Beraud  5 ,  Clara Fauveau  1  2  3  4  6 ,  Anna Y Belorusova  1  2  3  4 ,  Yassmine Chebaro  1  2  3  4 ,  Antonio Mouriño  7 ,  Thierry Massfelder  8 ,  Anne Chauchereau  9 ,  Daniel Metzger  1  2  3  4 ,  Natacha Rochel  1  2  3  4 ,  Gilles Laverny  1  2  3  4
Affiliations
  • 1. Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch-Graffenstaden, France.
  • 2. CNRS UMR 7104, Illkirch-Graffenstaden, France.
  • 3. Inserm U1258, Illkirch-Graffenstaden, France.
  • 4. University of Strasbourg, Illkirch-Graffenstaden, France.
  • 5. Urosphere, Toulouse, France.
  • 6. Transgene SA, Illkirch-Graffenstaden, France.
  • 7. Department of Chemistry, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • 8. INSERM U1260, Strasbourg, France.
  • 9. INSERM U981, Gustave Roussy, University of Paris-Saclay, Villejuif, France.
PMID: 38982588 DOI: 10.1111/bph.16492
Abstract

Background and purpose: Castration-resistant prostate Cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate Cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC.

Experimental approach: Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC.

Key results: Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with Cancer progression in the remaining cells.

Conclusion and implications: Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.

Keywords
castration resistant prostate cancer; docetaxel resistance; patient‐derived xenografts; spheroids; vitamin D analogues.
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