title: N-terminal targeting of androgen receptor variant enhances response of castration resistant prostate cancer to taxane chemotherapy.
abstract: Taxane-based chemotherapy is an effective treatment for castration-resistant-prostate cancer (CRPC) via stabilization of microtubules. Previous studies identified that the inhibitory effect of microtubule-targeting chemotherapy on androgen receptor (AR) activity was conferred by interfering with AR intracellular trafficking. The N-terminal domain (NTD) of AR was identified as a tubulin-interacting domain that can be effectively targeted by the novel small molecule inhibitor, EPI. Taken together this evidence provided the rationale that targeting AR nuclear translocation and activity via a combination of an antagonist of the AR NTD and taxane-based chemotherapy may enhance the therapeutic response in CRPC. The present study investigated the anti-tumor efficacy of a combination of EPI with Docetaxel chemotherapy, in cell models of CRPC, harboring the AR splice variants in addition to the full length AR. Our findings demonstrate that there was no significant effect on the androgen-mediated nuclear transport of AR variants and AR transcriptional activity by Docetaxel. The therapeutic response to Docetaxel was enhanced by inhibition of the NTD of AR (by EPI) through cycling of epithelial-mesenchymal-transition (EMT) to mesenchymal-epithelial-transition (MET) among prostate cancer epithelial cells. These results support that transient "programming" of EMT by the AR NTD inhibitor, potentially drives the sensitivity of prostate tumors with differential distribution of AR variants to microtubule-targeting chemotherapy. This study is of major significance in dissecting mechanisms to overcome taxane resistance in advanced CRPC.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Martin
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Banuelos
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Urology, University of Kentucky, Lexington, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA. Electronic address: nkypr2@uky.edu.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
keywords: Androgen signaling; Epithelial-mesenchymal transition; Prostate cancer; Taxanes; Therapeutic resistance