High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

Riikka Huhtaniemi; Petra Sipilä; Arttu Junnila; Riikka Oksala; Matias Knuuttila; Arfa Mehmood; Eija Aho; Teemu D Laajala; Tero Aittokallio; Asta Laiho; Laura Elo; Claes Ohlsson; Malin Hagberg Thulin; Pekka Kallio; Sari Mäkelä; Mika V J Mustonen; Matti Poutanen

doi:10.1016/j.isci.2022.104287

High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

iScience. 2022 Apr 25;25(5):104287. doi: 10.1016/j.isci.2022.104287. eCollection 2022 May 20.

Authors

Riikka Huhtaniemi¹, Petra Sipilä¹, Arttu Junnila¹, Riikka Oksala², Matias Knuuttila¹, Arfa Mehmood³, Eija Aho², Teemu D Laajala^{1

4

5}, Tero Aittokallio^{4

5}, Asta Laiho³, Laura Elo^{3

1}, Claes Ohlsson^{6

7}, Malin Hagberg Thulin⁶, Pekka Kallio², Sari Mäkelä^{1

8}, Mika V J Mustonen², Matti Poutanen^{1

6}

Affiliations

¹ Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
² Orion Corporation, Orion Pharma, Turku, Finland.
³ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
⁴ Department of Mathematics and Statistics, University of Turku, Turku, Finland.
⁵ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁶ Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁷ Region Västra Götaland, Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden.
⁸ Functional Foods Forum, University of Turku, Turku, Finland.

Abstract

Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.

Keywords: Cancer; Endocrinology.