Intracrine Androgen Biosynthesis and Drug Resistance

Overview

Journal Cancer Drug Resist

Date 2022 May 18

PMID 35582223

Authors

Trevor M Penning

Irfan A Asangani

Cynthia Sprenger

Stephen Plymate

Affiliations

Soon will be listed here.

Abstract

Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.

Citing Articles

Targeting sex steroid biosynthesis for breast and prostate cancer therapy.

Poutanen M, Hagberg Thulin M, Harkonen P Nat Rev Cancer. 2023; .

PMID: 37684402 DOI: 10.1038/s41568-023-00609-y.

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3.

Moller G, Temml V, Cala Peralta A, Gruet O, Richomme P, Seraphin D Metabolites. 2022; 12(2).

PMID: 35208174 PMC: 8876231. DOI: 10.3390/metabo12020099.

Downregulation of Dihydrotestosterone and Estradiol Levels by HEXIM1.

Mozar F, Sharma V, Gorityala S, Albert J, Xu Y, Montano M Endocrinology. 2021; 163(1).

PMID: 34864989 PMC: 8645165. DOI: 10.1210/endocr/bqab236.

References

Russell D, Wilson J . Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994; 63:25-61. DOI: 10.1146/annurev.bi.63.070194.000325. View

Antonarakis E, Lu C, Luber B, Wang H, Chen Y, Zhu Y . Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide. J Clin Oncol. 2017; 35(19):2149-2156. PMC: 5493048. DOI: 10.1200/JCO.2016.70.1961. View

Gazvoda M, Beranic N, Turk S, Burja B, Kocevar M, Rizner T . 2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3). Eur J Med Chem. 2013; 62:89-97. DOI: 10.1016/j.ejmech.2012.12.045. View

Chen S, Xu Y, Yuan X, Bubley G, Balk S . Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci U S A. 2006; 103(43):15969-74. PMC: 1635111. DOI: 10.1073/pnas.0604193103. View

He B, Bowen N, Minges J, Wilson E . Androgen-induced NH2- and COOH-terminal Interaction Inhibits p160 coactivator recruitment by activation function 2. J Biol Chem. 2001; 276(45):42293-301. DOI: 10.1074/jbc.M107492200. View

Knudsen K, Penning T . Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010; 21(5):315-24. PMC: 2862880. DOI: 10.1016/j.tem.2010.01.002. View

Hofland J, van Weerden W, Dits N, Steenbergen J, van Leenders G, Jenster G . Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 2010; 70(3):1256-64. DOI: 10.1158/0008-5472.CAN-09-2092. View

Stanbrough M, Bubley G, Ross K, Golub T, Rubin M, Penning T . Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006; 66(5):2815-25. DOI: 10.1158/0008-5472.CAN-05-4000. View

Taplin M, Bubley G, Shuster T, FRANTZ M, Spooner A, Ogata G . Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995; 332(21):1393-8. DOI: 10.1056/NEJM199505253322101. View

10.

Cannata D, Kirschenbaum A, Levine A . Androgen deprivation therapy as primary treatment for prostate cancer. J Clin Endocrinol Metab. 2011; 97(2):360-5. DOI: 10.1210/jc.2011-2353. View

11.

Fizazi K, Smith M, Tombal B . Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. Clin Genitourin Cancer. 2018; 16(5):332-340. DOI: 10.1016/j.clgc.2018.07.017. View

12.

Yang M, Xie W, Mostaghel E, Nakabayashi M, Werner L, Sun T . SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. J Clin Oncol. 2011; 29(18):2565-73. PMC: 3138634. DOI: 10.1200/JCO.2010.31.2405. View

13.

Paquet S, Fazli L, Grosse L, Verreault M, Tetu B, Rennie P . Differential expression of the androgen-conjugating UGT2B15 and UGT2B17 enzymes in prostate tumor cells during cancer progression. J Clin Endocrinol Metab. 2011; 97(3):E428-32. DOI: 10.1210/jc.2011-2064. View

14.

Takahashi R, Grigliatti T, Reid R, Riggs K . The effect of allelic variation in aldo-keto reductase 1C2 on the in vitro metabolism of dihydrotestosterone. J Pharmacol Exp Ther. 2009; 329(3):1032-9. DOI: 10.1124/jpet.109.150995. View

15.

Mohler J, Titus M, Bai S, Kennerley B, Lih F, Tomer K . Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011; 71(4):1486-96. PMC: 3075600. DOI: 10.1158/0008-5472.CAN-10-1343. View

16.

Tian Y, Zhao L, Zhang H, Liu X, Zhao L, Zhao X . AKR1C3 overexpression may serve as a promising biomarker for prostate cancer progression. Diagn Pathol. 2014; 9:42. PMC: 3939640. DOI: 10.1186/1746-1596-9-42. View

17.

Knudsen K, Scher H . Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009; 15(15):4792-8. PMC: 2842118. DOI: 10.1158/1078-0432.CCR-08-2660. View

18.

Clegg N, Wongvipat J, Joseph J, Tran C, Ouk S, Dilhas A . ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012; 72(6):1494-503. PMC: 3306502. DOI: 10.1158/0008-5472.CAN-11-3948. View

19.

Li Z, Bishop A, Alyamani M, Garcia J, Dreicer R, Bunch D . Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature. 2015; 523(7560):347-51. PMC: 4506215. DOI: 10.1038/nature14406. View

20.

Wangtrakuldee P, Adeniji A, Zang T, Duan L, Khatri B, Twenter B . A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics. J Steroid Biochem Mol Biol. 2019; 192:105283. PMC: 6625945. DOI: 10.1016/j.jsbmb.2019.01.001. View