Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide
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Julia Hoefer1, Mohammady Akbor1,2, Florian Handle1, Philipp Ofer1, Martin Puhr1, Walther Parson3,4, Zoran Culig1,5, Helmut Klocker1,*, Isabel Heidegger1,*
1Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Austria
2School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy
3Institute of Legal Medicine, Medical University of Innsbruck, Innsbruck, Austria
4Forensic Science Program, The Pennsylvania State University, University Park, Pennsylvania, USA
5Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne’s Hospital, Brno, Czech Republic
*Equally contributing senior authors
Helmut Klocker, email: [email protected]
Keywords: prostate cancer, enzalutamide resistance, androgen receptor, AR-V7, AR gene amplification
Received: March 02, 2016 Accepted: July 18, 2016 Published: July 29, 2016
Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation. After 10 months of cultivation, sustained growth in the presence of enzalutamide was achieved. When compared to controls, resistant cells exhibit significantly decreased sensitivity to enzalutamide as measured with 3[H]thymidine incorporation and WST assay. Moreover, these cell models exhibit partly re-activated AR signaling despite presence of enzalutamide. In addition, we show that enzalutamide resistant cells are insensitive to bicalutamide but retain considerable sensitivity to abiraterone. Mechanistically, enzalutamide resistance was accompanied by increased AR and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified.
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