Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Prostate. 2020 Feb;80(2):214-224. doi: 10.1002/pros.23935. Epub 2019 Dec 4.
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.
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 . 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.
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.
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.
紫杉烷类药物治疗可能是雄激素受体变体（AR-Vs）高表达的去势抵抗性前列腺癌患者的一种合适的治疗选择。本研究的目的是比较卡巴他赛和去势治疗在表达高水平组成型激活 AR-V7 的前列腺肿瘤异种移植模型中的疗效。此外，还探索了获得性卡巴他赛耐药的机制。
将 22Rv1 细胞皮下接种于小鼠，并用手术去势（n=7）、阿比特龙（n=9）、卡巴他赛（n=6）、去势联合阿比特龙（n=8）、去势联合卡巴他赛（n=11）或载体和/或假手术（n=23）处理。约 2 个月或肿瘤体积约 1000mm 3 时观察肿瘤生长情况。从卡巴他赛治疗期间复发的异种移植中建立了 2 个卡巴他赛耐药细胞系；22Rv1-CabR1 和 22Rv1-CabR2。通过全基因组表达谱分析，然后进行免疫印迹、免疫组化和功能途径分析，检测卡巴他赛耐药和对照 22Rv1 细胞之间的差异基因表达。
阿比特龙单独或联合手术去势治疗对 22Rv1 肿瘤生长无明显影响，而卡巴他赛单独或联合手术去势显著延迟并在某些情况下完全消除 22Rv1 肿瘤生长。2 个卡巴他赛耐药细胞系；22Rv1-CabR1 和 22Rv1-CabR2，均显示三磷酸腺苷结合盒亚家族 B 成员 1（ABCB1）外排泵的上调。ABCB1 抑制剂 elacridar 完全恢复了对卡巴他赛的敏感性，而 AR 拮抗剂比卡鲁胺和恩杂鲁胺的治疗部分恢复了 2 种细胞系对卡巴他赛的敏感性。22Rv1-CabR2 细胞系中胆固醇生物合成途径被诱导，这通过辛伐他汀治疗的敏感性降低得到证实。
尽管存在高水平的组成型激活 AR-V7，卡巴他赛仍能有效抑制前列腺癌的生长。涉及外排转运蛋白 ABCB1 过度表达的获得性卡巴他赛耐药可通过比卡鲁胺或恩杂鲁胺治疗逆转，表明卡巴他赛联合抗雄激素治疗具有巨大的临床潜力。
