Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-kB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer. Mol Cancer Ther; 13(5); 1270-84. Ó2014 AACR.

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Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation.

Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients’ clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.