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Overcoming drug resistance is critical for increasing the survival rate of prostate cancer (PCa). Doc‑ etaxel 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. | Schnepp et al. BMC Cancer 2021 21 1316 https doi.org 10.1186 s12885-021-09048-0 RESEARCH Open Access Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer Patricia M. Schnepp1 Aqila Ahmed1 June Escara Wilke1 Jinlu Dai1 Greg Shelley1 Jill Keller1 2 Atsushi Mizokami3 and Evan T. Keller1 2 4 5 Abstract Background Overcoming drug resistance is critical for increasing the survival rate of prostate cancer PCa . Doc etaxel 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 Pass ing 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 combi nation of TSA and docetaxel reduced tumor growth