Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
ACS Chem Biol. 2020 Mar 20;15(3):646-650. doi: 10.1021/acschembio.0c00069. Epub 2020 Mar 9.
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 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.
雄激素拮抗剂阿帕鲁胺和达罗鲁胺分别于 2018 年和 2019 年进入临床，用于治疗去势抵抗性前列腺癌（CRPC）。醛酮还原酶 1C3（AKR1C3）酶的表达增加是 CRPC 的表型特征。该酶通过产生强效雄激素来规避去势，从而促进增殖。此外，AKR1C3 介导对标准治疗药物恩扎鲁胺的化疗耐药，恩扎鲁胺是阿帕鲁胺的结构类似物。在开始治疗后的三个月内，几乎所有的 CRPC 患者都会产生耐药性。在此，我们报告阿帕鲁胺和结构不同的达罗鲁胺均可诱导前列腺癌细胞模型中 AKR1C3 的表达，并易发生 AKR1C3 介导的耐药性。用一种强效且高度选择性的 AKR1C3 抑制剂预处理可以逆转这种作用，使高表达 AKR1C3 的前列腺癌细胞系对这两种化疗药物更敏感，同时降低 AKR1C3 的表达和生物标志物前列腺特异性抗原。
