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Background The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC. Methods We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models. Results We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified  AURKB  and  KIF20A  as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher  AURKB  and  KIF20A  expression compared with a non-CBZ-resistant cell line. Inhibition of  AURKB  and  KIF20A  had an antitumor effect in DU145CR xenograft tumors. Higher expression of  AURKB  and  KIF20A  was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher  AURKB  and  KIF20A  expression. Conclusions Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting  AURKB  and  KIF20A .

Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening