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Transcription Factor Network Reveals New Treatments for Prostate Cancer Docetaxel Drug Resistance

ABSTRACT: Overcoming drug resistance is critical increasing the survival rate for prostate cancer (PCa). In this study, we modeled docetaxel resistance using two PCa cell lines, DU145 and PC3. We conducted both single cell and bulk RNA sequencing. We constructed a transcription factor (TF) network for the docetaxel sensitive and resistant variants for all cell lines and sequencing methods resulting in 8 networks. We identified shared edges and nodes that represent a shared TF network for PCa that modeled the changes after acquiring drug resistance. Using this shared TF network, we identified drivers of the resistant phenotype. Interestingly, the network constructed from the bulk sequencing dataset revealed different TF drivers of resistance compared with the network constructed from the single cells. We validated the results constructed from the single cells to demonstrate the validity of the single cell sequenced TF network. We targeted GABPA (only identified in the single cell constructed network) and successfully re-sensitized both cell lines to docetaxel treatment. Additionally, we conducted connectivity map analysis to identify potential drugs that disrupt the resistant networks. We identified trichostatin A as a potential combination treatment using the single cell sequenced network. Combination treatment of trichostatin A and docetaxel, both in vitro and in vivo PCa models decreased tumor growth. These results suggest by analyzing a population of resistant cells, identification of drivers and novel treatments is possible.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149681 | GEO | 2023/04/01

REPOSITORIES: GEO

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Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments

Project description:Docetaxel is used as a standard treatment in patients with metastatic castration-resistant prostate cancer. However, a large subset of patients develops resistance by mechanisms that remain largely unknown. It is thus important to define the relevant pathways implicated in docetaxel-resistance and validate predictive biomarkers that will allow approaches of personalized treatment. In this aim, we established resistant IGR-CaP1 prostate cancer cell lines to different doses of docetaxel (IGR-CaP1-R cell lines) and investigated gene expression profiles by microarray analyses. We generated a signature of 112 genes potentially implicated in docetaxel-resistance whose expression is highly modified (Fold change M-bM-^IM-% 5). Among these genes, significant modification of expression was observed among cell cycle components in the resistant cells. Hence, we focused on the role of the cell cycle regulator LZTS1 located on chromosome 8p which was under-expressed in all our docetaxel-resistant models. LZTS1 extinction was confirmed at the RNA and protein levels. DNA methylation analysis revealed a stretch of 20 highly methylated CpGs in the region encompassing the exon 1 of LZTS1 promoter in the docetaxel-resistant cells suggesting the existence of an epigenetic regulation of LZTS1 expression in the resistant cells. By using siRNA strategy, we found evidence that LZTS1 plays an important role in the acquisition of the resistant phenotype. In addition, immunohistochemical staining showed that LZTS1 protein was absent or down-regulated in 33% of diagnostic biopsies obtained in patients with metastatic castration-resistant prostate cancer. This heterogeneous labeling suggests that LZTS1 might constitute a predictive biomarker of response to docetaxel chemotherapy. Furthermore, as Cdc25C is a LZTS1 partner in the mitosis regulation, we observed that targeting of Cdc25C with the pharmacological Cdc25C inhibitor NSC 663284 specifically killed the docetaxel-resistant cells. These results strongly suggest that Cdc25C plays a role in docetaxel resistance and that Cdc25C might be a therapeutic target to overcome docetaxel resistance. Altogether our findings identify an important role of LZTS1 in developing docetaxel resistance in prostate cancer through its role in regulating phosphatase Cdc25C. The set of gene expression with 4x44K Agilent ( design 014850) correspond to 6 doses of docetaxel 2?5 to 200 ug/ml) in dual color and dye-swap versus the IGR-Cap1 cell line without docetaxel.

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Transcription Factor Network Reveals New Treatments for Prostate Cancer Docetaxel Drug Resistance

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