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. 2024 Nov;181(21):4279-4293.
doi: 10.1111/bph.16492. Epub 2024 Jul 9.

A vitamin D-based strategy overcomes chemoresistance in prostate cancer

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

A vitamin D-based strategy overcomes chemoresistance in prostate cancer

Kateryna Len-Tayon et al. Br J Pharmacol. 2024 Nov.

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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