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Updated: Oct 10, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel
Patricia M Schnepp1, Aqila Ahmed1, June Escara-Wilke1
1Department of Urology, University of Michigan Medical School, NCRC B14 RM116, Ann Arbor, MI, 48109, USA.
Background:
Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). Docetaxel is the first cytotoxic chemotherapeutical approved for treatment of PCa. However, 99% of PCa patients will develop resistance to docetaxel within 3 years. Understanding how resistance arises is important to increasing PCa survival.
Methods:
In this study, we modeled docetaxel resistance using two PCa cell lines: DU145 and PC3. Using the Passing Attributes between Networks for Data Assimilation (PANDA) method to model transcription factor (TF) activity networks in both sensitive and resistant variants of the two cell lines. We identified edges and nodes shared by both PCa cell lines that composed a shared TF network that modeled changes which occur during acquisition of docetaxel resistance in PCa. We subjected the shared TF network to connectivity map analysis (CMAP) to identify potential drugs that could disrupt the resistant networks. We validated the candidate drug in combination with docetaxel to treat docetaxel-resistant PCa in both in vitro and in vivo models.
Results:
In the final shared TF network, 10 TF nodes were identified as the main nodes for the development of docetaxel resistance. CMAP analysis of the shared TF network identified trichostatin A (TSA) as a candidate adjuvant to reverse docetaxel resistance. In cell lines, the addition of TSA to docetaxel enhanced cytotoxicity of docetaxel resistant PCa cells with an associated reduction of the IC50 of docetaxel on the resistant cells. In the PCa mouse model, combination of TSA and docetaxel reduced tumor growth and final weight greater than either drug alone or vehicle.
Conclusions:
We identified a shared TF activity network that drives docetaxel resistance in PCa. We also demonstrated a novel combination therapy to overcome this resistance. This study highlights the usage of novel application of single cell RNA-sequencing and subsequent network analyses that can reveal novel insights which have the potential to improve clinical outcomes.
Insights
Drug resistance in prostate cancer (PCa) is a major challenge. This study identified a shared transcription factor network driving docetaxel resistance and found trichostatin A (TSA) can reverse it, improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Prostate cancer (PCa) treatment faces challenges due to drug resistance, particularly to docetaxel, a primary chemotherapy.
- Understanding the mechanisms of docetaxel resistance is crucial for improving PCa patient survival rates.
Purpose of the Study:
- To model and understand the molecular networks underlying docetaxel resistance in PCa.
- To identify potential therapeutic strategies to overcome docetaxel resistance in PCa.
Main Methods:
- Utilized the Passing Attributes between Networks for Data Assimilation (PANDA) method to model transcription factor (TF) activity networks in docetaxel-sensitive and resistant PCa cell lines.
- Identified a shared TF network common to both cell lines to model resistance acquisition.
- Employed Connectivity Map Analysis (CMAP) to identify drugs targeting the resistant TF network.
- Validated candidate drugs in combination with docetaxel using in vitro and in vivo PCa models.
Main Results:
- A shared TF network implicated 10 key TF nodes in docetaxel resistance development.
- CMAP analysis identified trichostatin A (TSA) as a potential drug to reverse docetaxel resistance.
- Combination therapy with TSA and docetaxel demonstrated enhanced cytotoxicity in resistant PCa cells and reduced tumor growth in a PCa mouse model compared to monotherapy.
Conclusions:
- A conserved transcription factor activity network driving docetaxel resistance in prostate cancer was identified.
- A novel combination therapy using TSA and docetaxel was demonstrated to overcome docetaxel resistance.
- The study highlights the utility of single-cell RNA-sequencing and network analyses for uncovering therapeutic strategies to improve clinical outcomes in PCa.
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