In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3444-3444
Abstract:
Castration resistant prostate cancer (CRPC) treatment aims to stop a resurgence of androgen receptor (AR) signaling with a class of therapeutics known as androgen receptor signaling inhibitors (ARSI). Through inhibition of CYP17A1, Abiraterone (Abi) prevents an upstream step in androgen biosynthesis, while Enzalutamide (ENZ) acts as an AR antagonist. Despite the early success of ARSI, a subset of patients develop resistance and succumb to the disease. One major mode of resistance is thought to occur when steroidogenic enzymes that are upregulated in CRPC convert weaker circulating precursors to testosterone (T) and dihydrotestosterone (DHT) to restore AR signaling. In this study, we identify a mechanism driving intratumoral steroidogenesis that involves AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase type 5). AKR1C3 is a major steroidogenic enzyme in the prostate that is involved in all androgen biosynthetic pathways to T and DHT, upregulated in CRPC patients, and is a component of Abi and ENZ drug resistance. Previously with Taplin et al. we observed in patients on Leuprolide that T was reduced to 5 ng/dL, and the addition of Abi lowered DHEA-S by 90% (from 230,000 ng/dL to 22,000 ng/dL). However, the DHEA-S that remained was 4,000x greater than circulating T, making it a reservoir for intratumoral steroidogenesis post Abi treatment. Here, we demonstrate that post-Abi concentrations of DHEA-S, and castrate levels of DHEA-S (post-leuprolide but pre-Abi treatment), which also corresponds to DHEA-S levels patients on ENZ are 1) converted to T in an AKR1C3-dependent manner in prostate cancer (PCa) cells, and 2) sufficient to stimulate AKR1C3-dependent cell growth. Our observations are consistent across both primary and metastatic PCa cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made using our highly sensitive and specific stable isotope dilution liquid chromatography tandem mass spectrometry (SID-LC-MS/MS) method. Additionally, we demonstrate AKR1C3-dependence using genetic and pharmacological approaches with an AKR1C3 stable knockdown for each cell line and two AKR1C3 competitive inhibitors. Taken together, we have identified a mechanism of resistance to ARSIs common to both primary and metastatic cell lines that operates through AKR1C3’s intratumoral conversion of DHEA-S to potent androgens that drive prostate cancer growth. Citation Format: Andrea J. Detlefsen, Ling Duan, Clementina Mesaros, Trevor M. Penning. Role of AKR1C3 in converting reservoirs of DHEA-S into potent androgens that drive prostate cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3444.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-3444
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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