AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

Abstract

Background Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration‐resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to these therapies within 2 years. JNJ‐pan‐AR is a broad‐spectrum AR antagonist that inhibits wild‐type AR as well as several mutated versions of AR that have emerged in patients on chronic antiandrogen treatment. In this work, we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ‐pan‐AR treatment. Methods The LNCaP JNJR prostate cancer subline was developed by chronically exposing LNCaP parental cells to JNJ‐pan‐AR. Transcriptomic and proteomic profiling was performed to identify potential drivers and/or biomarkers of the resistant phenotype. Results Several enzymes critical to intratumoral androgen biosynthesis, Aldo‐keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17 were identified as potential upstream regulators of the JNJ‐pan‐AR resistant cells. While we confirmed the overexpression of all three enzymes in the resistant cells only AKR1C3 expression played a functional role in driving JNJ‐pan‐AR resistance. We also discovered that AKR1C3 regulates UGT2B15 and UGT2B17 expression in JNJ‐pan‐AR resistant cells. Conclusions This study supports the rationale to further investigate the benefits of AKR1C3 inhibition in combination with antiandrogens to prevent CRPC disease progression.

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

“…When multiple steroids ( HSD3B2 , AKR1C3 , CYP17A1 , and CYP11A1 ) are present [ 28 , 29 , 30 , 31 ], adrenal androgen precursors can be used to promote DHT synthesis within tumors through the 5α-diketone pathway, leading to dehydroepiandrosterone (DHEA) and androstenedione conversion into DHT without any requirement for testosterone [ 32 , 33 , 34 , 35 ]. Abiraterone is a specific inhibitor of CYP17A1, and it was also the first drug approved to treat CRPC [ 32 , 36 ].…”