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Updated: Nov 28, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
AKR1C3 mediates pan-AR antagonist resistance in castration-resistant prostate cancer
Jennifer R Hertzog1,2, Zhuming Zhang3, Gilles Bignan3
1Discovery Oncology, Janssen R&D US, Spring House, Pennsylvania.
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.
Insights
Chronic JNJ-pan-AR treatment in prostate cancer cells identified Aldo-keto reductase family 1 member C3 (AKR1C3) as a key driver of resistance. Inhibiting AKR1C3 may prevent castration-resistant prostate cancer progression when combined with antiandrogens.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Antiandrogen therapies are crucial for treating castration-resistant prostate cancer (CRPC).
- Resistance to antiandrogens, including JNJ-pan-AR, develops in a significant portion of CRPC patients.
- Understanding resistance mechanisms is vital for improving CRPC treatment outcomes.
Purpose of the Study:
- To investigate the mechanisms of resistance to JNJ-pan-AR, a broad-spectrum androgen receptor (AR) antagonist.
- To identify potential drivers and biomarkers associated with JNJ-pan-AR resistance in prostate cancer.
Main Methods:
- Development of a JNJ-pan-AR resistant prostate cancer cell line (LNCaP JNJR) through chronic drug exposure.
- Comprehensive transcriptomic and proteomic profiling of parental and resistant cell lines.
Main Results:
- Overexpression of enzymes involved in intratumoral androgen biosynthesis, including Aldo-keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17, was observed in resistant cells.
- AKR1C3 was identified as the primary functional driver of JNJ-pan-AR resistance.
- AKR1C3 was found to regulate the expression of UGT2B15 and UGT2B17 in resistant cells.
Conclusions:
- AKR1C3 plays a critical role in mediating resistance to JNJ-pan-AR in prostate cancer.
- Inhibition of AKR1C3, in combination with antiandrogens, warrants further investigation for preventing CRPC progression.
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