title: Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer.
abstract: Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Martin
authors.affiliation: Department of Urology, University of Kentucky, Lexington, Kentucky.
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.affiliation: Department of Urology, University of Kentucky, Lexington, Kentucky.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Penticuff
authors.affiliation: Department of Urology, University of Kentucky, Lexington, Kentucky.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky. Department of Pathology and Laboratory Medicine, Lexington, Kentucky. Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky. Department of Urology, University of Kentucky, Lexington, Kentucky. Department of Pathology and Laboratory Medicine, Lexington, Kentucky. Markey Cancer Center, University of Kentucky, Lexington, Kentucky. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky. nkypr2@email.uky.edu.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000726:Androgen Antagonists; D043823:Taxoids; C552428:cabazitaxel