Abstract
BackgroundOvercoming 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.MethodsIn 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.ResultsIn 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.ConclusionsWe 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.
Highlights
Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa)
Identifying network enriched edges We initially conducted single cell RNA-sequencing on two PCa cell lines, DU145 and PC3, that had been previously created to be resistant to docetaxel treatment [9]
PANDA integrates the gene-gene co-expression information from each of the four established cell lines with an initial regulatory network consisting of 240 transcription factor (TF) as well as known TF-TF interactions and TF-Gene interactions [25]
Summary
Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). A taxane, was one of the first cytotoxic therapies approved for CRPC in the United States [3]. It operates through the stabilization of microtubules and inhibition of Bcl-2 expression [4,5,6]. The survival benefits of docetaxel are limited with resistance developing in nearly 99% of patients within 3 years [7]. Understanding how this resistance arises is critical to identify strategies to overcome resistance and increase the survival of PCa patients
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