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Volume 13
Issue 12
10.3390/cancers13122939
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Article

Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients

by
Nada Lallous
†,
Oliver Snow
,
Christophe Sanchez
‡,
Ana Karla Parra Nuñez
‡,
Bei Sun
‡,
Ahmed Hussain
,
Joseph Lee
,
Helene Morin
,
Eric Leblanc
,
Martin E. Gleave
and
Artem Cherkasov
*,†
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada
*
Author to whom correspondence should be addressed.
†
Lallous and Cherkasov labs contributed equally to this work.
‡
Authors equally contributed to the work.
Academic Editor: Vasiliki Tzelepi
Cancers 2021, 13(12), 2939; https://doi.org/10.3390/cancers13122939
Received: 22 May 2021 / Revised: 4 June 2021 / Accepted: 8 June 2021 / Published: 11 June 2021
(This article belongs to the Collection Prostate Cancer: Pathophysiology, Pathology and Therapy)
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Simple Summary

Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-related death. The driver of PCa proliferation and growth is the androgen receptor (AR) and inhibiting this receptor is the standard of care for patients, following surgery or radiotherapy. Unfortunately, the effectiveness of current therapeutics is temporary, with the cancer eventually developing drug resistance. Among the mechanisms of resistance are the arising mutations in the AR that make the receptor promiscuously activated by drugs or non-specific ligands, thus promoting cancer progression. The aim of this study is to characterize the responses of 44 AR mutants, derived from PCa patients, to available steroids that activate the receptor as well as to various treatments currently used in the clinic. This work will help create a tool to guide the medical team in selecting the best personalized treatment option for each patient.

Abstract

Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the effect of darolutamide to a total of 68 AR mutants. Unlike other AR antagonists, we demonstrate that darolutamide exhibits consistent efficiency against all characterized gain-of-function mutations in a full-length AR. Additionally, the response of the AR mutants to clinically used bicalutamide and enzalutamide, as well as to major endogenous steroids (DHT, estradiol, progesterone and hydrocortisone), was also investigated. As genomic profiling of PCa patients becomes increasingly feasible, the developed “AR functional encyclopedia” could provide decision-makers with a tool to guide the treatment choice for PCa patients based on their AR mutation status. View Full-Text
Keywords: androgen receptor; antagonists; castration-resistant prostate cancer (CRPC); darolutamide; drug resistance; mutations androgen receptor; antagonists; castration-resistant prostate cancer (CRPC); darolutamide; drug resistance; mutations
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MDPI and ACS Style

Lallous, N.; Snow, O.; Sanchez, C.; Parra Nuñez, A.K.; Sun, B.; Hussain, A.; Lee, J.; Morin, H.; Leblanc, E.; Gleave, M.E.; Cherkasov, A. Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients. Cancers 2021, 13, 2939. https://doi.org/10.3390/cancers13122939

AMA Style

Lallous N, Snow O, Sanchez C, Parra Nuñez AK, Sun B, Hussain A, Lee J, Morin H, Leblanc E, Gleave ME, Cherkasov A. Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients. Cancers. 2021; 13(12):2939. https://doi.org/10.3390/cancers13122939

Chicago/Turabian Style

Lallous, Nada, Oliver Snow, Christophe Sanchez, Ana K. Parra Nuñez, Bei Sun, Ahmed Hussain, Joseph Lee, Helene Morin, Eric Leblanc, Martin E. Gleave, and Artem Cherkasov. 2021. "Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients" Cancers 13, no. 12: 2939. https://doi.org/10.3390/cancers13122939

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