pci-32765 and Prostatic-Neoplasms--Castration-Resistant

Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity

Topics: Adenine; Amino Acid Motifs; Androgen Antagonists; Androgens; Animals; Antibodies; Cell Line, Tumor; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Male; Mice; Mice, Inbred ICR; Mice, SCID; Neoplasm Transplantation; Phosphorylation; Piperidines; Prostatic Neoplasms, Castration-Resistant; Protein Binding; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, Androgen; Sequence Analysis, RNA; Signal Transduction; Tissue Array Analysis