Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti‐androgens

Abstract

BackgroundTaxane 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.MethodsMice 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 mm3. 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.ResultsAbiraterone 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.ConclusionsCabazitaxel 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.

Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p

“…To assess whether abiraterone could upregulate SLCO1B3 in vivo, we treated mice bearing 22Rv1 xenografts with abiraterone acetate or vehicle control for either 5 or 15 days. As anticipated abiraterone treatment did not reduce the growth of 22Rv1 xenografts (data not shown), consistent with previous studies 26 , 29 . After 5 days of abiraterone acetate treatment, tumors were excised and digested to measure mRNA transcripts.…”

Clinicopathological characteristics of androgen receptor splicing variant 7 (AR-V7) expression in patients with castration resistant prostate cancer: A systematic review and meta‐analysis

“…According to a recent study published in 2019, prostate cancer is the most common cancer among American men [1] . Unfortunately, most cases of prostate cancer eventually progress to metastatic castration-resistant prostate cancer (mCRPC) [ 2 , 3 ]. There is a need to identify predictive biomarkers for worse prognosis and to develop precise therapeutic options.…”

Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel‐resistant prostate cancer

“…Patients with AR splicing variant V7 (AR‐V7)‐positive metastatic CRPC showed better outcome when treated with taxanes, DOC, and CBZ, rather than androgen‐signaling‐targeted inhibitors, enzalutamide or abiraterone 22 . There has also been a report showing that susceptibility to AR‐antagonists was restored in CBZ‐resistant cells established from androgen‐refractory 22Rv1 cells and a similar phenomenon was observed in clinical practice 23 . To recapitulate clinical manifestations of CBZ‐resistance, we established DOC‐resistant 22Rv1DR cells from CRPC 22Rv1 cells expressing both AR and AR‐V7, from which CBZ‐resistant 22Rv1CR cells were developed.…”