In PC3 and DU145 cells was much stronger PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28192408 (approximately 50 ). LNCaP cells,

In PC3 and DU145 cells was much stronger PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28192408 (approximately 50 ). LNCaP cells, which express a much lower level of uPA, also showed a reduction upon dasatinib treatment. When we extended the same drug treatment study in three resistant cell lines, 22Rv, VCaP and MDAPCa2b (Figure 3c), the magnitude of uPA reduction by dasatinib was correlated nicely with the sensitivity of cells to dasatinib (r = 0.72), with the highest reduction seen in the most sensitive cell line. This suggests uPA is a potential surrogate biomarker for the biological effect of dasatinib. Furthermore, in a multiple-dose treatment study with PC3 cells, we found that the reduction of uPADiscussionThe ideal scenario for identifying biomarkers for clinical use is to use samples obtained from patients undergoing therapy with the investigational drug and to analyze gene expression data in the context of patient response data. Since dasatinib isGenome Biology 2007, 8:Rhttp://genomebiology.com/2007/8/11/RGenome Biology 2007,Volume 8, Issue 11, Article RWang et al. R255.Figure 3 protein levels uPA gene expression and regulation by dasatinib analyzed at mRNA and uPA gene expression and regulation by dasatinib analyzed at mRNA and protein levels. (a) Differential baseline expression of uPA gene between resistant (R, in black) and sensitive (S, in red) cell lines. The x-axis values are the expression level in log2-scale. The resistant cell line expressing a high level of uPA was WPMY1 and the sensitive cell line expressing a low level of uPA was LNCaP. (b) Down-regulation of uPA mRNA level by dasatinib treatment in five sensitive cell lines. The cells were treated with 100 nM dasatinib (+D) or DMSO (Ctrl) for 48 h. The p value was 0.048 by paired t-test, indicating a significant reduction of uPA mRNA following dasatinib treatment. (c) Correlation between dasatinib-induced uPA mRNA down-regulation with the sensitivity of cell lines to dasatinib. In addition to the five sensitive cell lines, three dasatinib-resistant cell lines, 22Rv, MDAPCa2b, and VCaP, were also treated with dasatinib as in (b). The extent of uPA down-regulation by dasatinib (y-axis) was negatively correlated with the log2IC50 values (x-axis) of these eight cell lines. (d) Dose-dependent down-regulation of uPA mRNA expression in PC3 cells. Cells were treated with or without different concentrations of dasatinib for 4 or 24 h. The uPA expression level relative to control is shown on the y-axis. (e) Dose-dependent inhibition of secreted uPA protein in PC3 cells by dasatinib but not by paclitaxel. Cells were treated with different doses of dasatinib, paclitaxel or DMSO for 24 h. The amount of uPA protein secreted into the culture medium by 50,000 viable cells was assessed by ELISA assay.Figurea novel agent in early clinical development, using preclinical models to identify candidate biomarkers for assisting clinical development appears the best option. In this study, we used 16 prostate cell lines to identify biomarkers that were correlated with the sensitivity of cells and with the mechanisms of drug ABT-737 web action. These biomarkers could potentially be used for predicting and monitoring dasatinib response. In particular, we identified five genes (AR, PSA, CK5, uPA and EphA2) that were highly associated with drug sensitivity/ resistance and/or modulated by drug treatment. Consistent with our observation in breast cancer cell lines [8], it appears that basal-type prostate cancer cells expressing low levels of AR and PSA and a.