Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti‐androgens. Issue 2 (4th December 2019)

• Record Type: Journal Article
• Authors: Ylitalo, Erik Bovinder; Thysell, Elin; Thellenberg‐Karlsson, Camilla; Lundholm, Marie; Widmark, Anders; Bergh, Anders; Josefsson, Andreas; Brattsand, Maria; Wikström, Pernilla
• Is Part Of: Prostate. Volume 80:Issue 2(2020)
• Page Start: 214
• Page End: 224
• Publication Date: 2019-12-04
• Subjects: ABCB1 -- androgen receptor -- cabazitaxel -- cholesterol -- prostate cancer -- splice variant; Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.23935
• Languages: English
• ISSNs: 0270-4137

Abstract

Abstract: Background: Taxane treatment may be a suitable therapeutic option for patients with castration‐resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR‐Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR‐V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored. Methods: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration ( n = 7), abiraterone ( n = 9), cabazitaxel ( n = 6), castration plus abiraterone ( n = 8), castration plus cabazitaxel ( n = 11), or vehicle and/or sham operation ( n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm 3 . Two cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole‐genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis. Results: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, both showed upregulation of the ATP‐binding cassette sub‐family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR‐antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1‐CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment. Conclusions: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR‐V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti‐androgens.