Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor.

Abstract	The antiandrogen therapeutics apalutamide and darolutamide entered the clinic in 2018 and 2019, respectively, for the treatment of castration-resistant prostate cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 (AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by producing potent androgens that drive proliferation. Furthermore, AKR1C3 mediates chemotherapeutic resistance to the standard of care, enzalutamide, a structural analogue of apalutamide. Resistance develops in almost all CRPC patients within three months of beginning treatment. Herein, we report that both apalutamide and the structurally distinct darolutamide induce AKR1C3 expression in in vitro models of prostate cancer and are susceptible to AKR1C3-mediated resistance. This effect is countered by pretreatment with a potent and highly selective AKR1C3 inhibitor, sensitizing high AKR1C3 expressing prostate cancer cell lines to the action of both chemotherapeutics with a concomitant reduction in expression of AKR1C3 and the biomarker prostate-specific antigen.
Authors	Ahmed Morsy, Paul C Trippier
Journal	ACS chemical biology (ACS Chem Biol) Vol. 15 Issue 3 Pg. 646-650 (03 20 2020) ISSN: 1554-8937 [Electronic] United States
PMID	32125151 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Androgen Antagonists Antineoplastic Agents Benzamides Enzyme Inhibitors Nitriles Pyrazoles Thiohydantoins apalutamide darolutamide Phenylthiohydantoin enzalutamide Aldo-Keto Reductase Family 1 Member C3 Prostate-Specific Antigen
Topics	Aldo-Keto Reductase Family 1 Member C3 (genetics, metabolism) Androgen Antagonists (metabolism) Antineoplastic Agents (metabolism) Benzamides Cell Line, Tumor Cell Proliferation (drug effects) Drug Discovery Drug Resistance, Neoplasm (drug effects) Drug Therapy, Combination Enzyme Inhibitors (metabolism) Gene Expression Regulation (drug effects) Humans Male Nitriles Orchiectomy Phenylthiohydantoin (analogs & derivatives, metabolism) Prostate-Specific Antigen (metabolism) Prostatic Neoplasms, Castration-Resistant (drug therapy) Pyrazoles (metabolism) Substrate Specificity Thiohydantoins (metabolism)

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