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 EMTMET 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 912-926 |
| Number of pages | 15 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 4 |
| DOIs | |
| State | Published - Feb 15 2016 |
Funding
The authors thank Lorie Howard for her assistance in the submission of the manuscript,Dr. Patrick Hensley for his expert assistance with the preparation of the figures, and Dr. Stephen E. Strup (Department of Urology, University of Kentucky, Lexington, KY) for useful discussions. This work was supported by funding from Sanofi-Aventis Pharmaceuticals, an NIH/NIDDK R01 DK 083761 grant and the James F. Hardymon Endowment in Urological Research at the University of Kentucky (Lexington, KY). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
ASJC Scopus subject areas
- Oncology
- Cancer Research
