Androgens2016 Poster Presentations (1) (42 abstracts)
Critical Role of Androgen Receptor Level in Prostate Cancer Cell Resistance to New Generation Antiandrogen Enzalutamide
Julia Hoefer 1 , Mohammady Akbor 1, , Florian Handle 1 , Philipp Ofer 1 , Martin Puhr 1 , Walther Parson 3, , Zoran Culig 1, , Helmut Klocker 1 & Isabel Heidegger 1
1Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria; 2School of Biosciences and Veterinary Medicine, University of 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
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 insensitivities 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 in the presence of increasing concentrations of the enzalutamide (up to 8 μM], sustained growth of resistant sub cell-lines 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 full length and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified.
Funding: Krebshilfe Tyrol grant to IH, MUI start program to IH and FWF grant T 738-BBL to JH.
Presenting Author: Julia Hoefer, Department of Urology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. Email: [email protected]
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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