Authors:
 Jennifer R. Hertzog MS, Zhuming Zhang PhD, Gilles Bignan PhD, Peter J. Connolly PhD, Jason E. Heindl PhD, Christopher J. Janetopoulos PhD, Brent A. Rupnow PhD, Theresa M. McDevitt PhD
 
 
 Affiliations:
 Discovery Oncology, Janssen R&D US, PA; Department of Biological Sciences, University of the Sciences in Philadelphia, PA; Discovery Chemistry, Janssen R&D US,PA
 
 
 Abstract Body:
 Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of CRPC patients. However, an estimated 30% of responders will develop resistance to these therapies within two 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 anti-androgen treatment. In this work we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ-pan-AR exposure. We generated a subline of LNCaP cells that are resistant to JNJ-pan-AR by chronic exposure in vitro. We performed comprehensive transcriptomic and proteomic profiling to identify potential drivers and/ or biomarkers of the resistant phenotype. Several enzymes critical to intratumoral androgen biosynthesis, 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. Previous reports have shown that AKR1C3 confers resistance to second-generation AR antagonist inhibitors. In addition, we confirmed that AKR1C3 protein expression is up-regulated across LNCaP and LNCaP/AR cell lines that are resistant to either enzalutamide or apalutamide. We also confirmed that AR-v7 mRNA expression is upregulated in several prostate cancer cell lines that are resistant to JNJ-pan-AR which is an observation that has been identified in preclinical models as well as in clinical samples from patients with acquired resistance to AR antagonist treatment. In sum, a key finding from this study is that AKR1C3 expression is upregulated when cells are chronically exposed to several different second-generation AR inhibitors rendering it a PAN-induced target of resistance. Collectively, these data strongly support the incorporation of an AKR1C3 inhibitor to counter resistance to second-generation AR antagonists.
 
 
 Funding Acknowledgments:
 Janssen R&D
 
 
 Corresponding Author Email:
 jhertzo@its.jnj.com
 
 
 Conflict of Interest:
 Nothing to Disclose

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