Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Hongo H

PROVIDER: S-EPMC10023558 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Hongo Hiroshi H Kosaka Takeo T Suzuki Yoko Y Oya Mototsugu M

Prostate cancer and prostatic diseases 20210930 1

<h4>Background</h4>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.<h4>Methods</h4>We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 ce ...[more]

PMID: 34593983

Similar Datasets

Project description:BackgroundSeveral studies have reported the efficacy of cabazitaxel in cancer therapy; however, investigations of its safety are few. The aim of this study was to retrospectively analyze the efficacy and safety of cabazitaxel based on treatment outcome data.MethodsA questionnaire form on the use of cabazitaxel was mailed to hospitals associated with the Shinshu University. Responses were received from 11 institutions regarding 55 cases.ResultsPatients received a median of 4 courses of cabazitaxel treatment. Decreases in prostrate-specific antigen (PSA) were observed in 61.5% of cases with declines of 30%, 50%, and 90% in 36.5%, 23.0%, and 7.6% of cases, respectively. PSA progression-free survival was 5.0 months, and overall survival after the start of cabazitaxel was 13.0 months. Forty-five patients received postcabazitaxel treatment; 17 showed decreased PSA. Safety assessment indicated that white blood cell and neutrophil counts were significantly higher in the second than in the first course of treatment and Grade 3 to 4 leukopenia and neutropenia significantly decreased. Twenty-four subjects were aged ≥75 years; 79% of them had their doses reduced at the first administration. The mean dose was 20 mg/m2. However, there was no significant difference in the PSA progression-free survival between the ≥75-year-old and <75-year-old groups. Patients in the ≥75-year-old group, particularly those whose doses were not reduced, experienced several Grade 3 to 4 adverse effects. Ten patients discontinued treatment owing to adverse effects and systemic worsening.ConclusionsTo use cabazitaxel effectively, starting administration as early as possible before disease progression is important, and even if Grade 3 to 4 leukopenia and neutropenia are observed during the first course, it is important to carefully maintain the dose. Even when treating elderly patients, reducing the dose does not reduce therapeutic efficacy. However, because this cohort experienced several ≥ Grade 3 adverse effects, a great deal of caution is required.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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