The Crucial Role of AR-V7 in Enzalutamide-Resistance of Castration-Resistant Prostate Cancer

Abstract

Prostate cancer (PCa) has the second highest incidence of malignancies occurring in men worldwide. The first-line therapy of PCa is androgen deprivation therapy (ADT). Nonetheless, most patients progress to castration-resistant prostate cancer (CRPC) after being treated by ADT. As a second-generation androgen receptor (AR) antagonist, enzalutamide (ENZ) is the current mainstay of new endocrine therapies for CRPC in clinical use. However, almost all patients develop resistance during AR antagonist therapy due to various mechanisms. At present, ENZ resistance (ENZR) has become challenging in the clinical treatment of CRPC. AR splice variant 7 (AR-V7) refers to a ligand-independent and constitutively active variant of the AR and is considered a key driver of ENZR in CRPC. In this review, we summarize the mechanisms and biological behaviors of AR-V7 in ENZR of CRPC to contribute novel insights for CRPC therapy.

Identifying new driver genes for castration resistance for prostate cancer based on protein mass spectrometry and transcriptome big data

“…Within the marker genes with top number of downstream genes, AR was the gene mostly reported and accepted for castration resistance 8 . The variants for AR, especially AR-V7, played central role on castration resistance [11][12][13] . Within the other top marker genes, FOXA1, EPCAM, EGFR and TP53 were reported and well studied for castration resistance [38][39][40] , while however PRPF6 was with highest number of downstream genes within the less reported genes for castration resistance (Fig.…”

“…The mechanism for AR driving potential might include generation of ligand independent splicing variants, abnormal ampli cation for AR gene and in uence of AR co-regulatory molecules 9,10 . AR variant AR-V7 also played important role and was regarded as the driver for the formation of castration resistance for prostate cancer [11][12][13] . Meanwhile, prostate cancer microenvironment was studied for progression and drug resistance generation for CRPC and microenvironment factors including IL23 were reported to promote CRPC [14][15][16][17] .…”

Development of a Double-Stapled Peptide Stabilizing Both α-Helix and β-Sheet Structures for Degrading Transcription Factor AR-V7

“…AR-V7 is a truncated form of the androgen receptor (AR) protein lacking the ligand-binding domain (LBD), which is responsible for binding to androgens like testosterone and dihydrotestosterone. , Its role in the development and progression of castration-resistant prostate cancer (CRPC), a form of prostate cancer resistant to androgen deprivation therapy (ADT), has been extensively studied. , Despite significant advancements in the use of small molecules targeting AR-V7 in recent years, no drugs specifically targeting AR-V7 have been approved for clinical use thus far. This unmet clinical need underscores the necessity for alternative approaches to effectively target AR-V7.…”

Aldo-Keto Reductase 1C3 Inhibitor Prodrug Improves Pharmacokinetic Profile and Demonstrates In Vivo Efficacy in a Prostate Cancer Xenograft Model

“…22 AKR1C3 has been shown to contribute to chemotherapeutic resistance in CRPC since its expression is increased in enzalutamide and abiraterone acetate-resistant PCa cell lines. 23−25 An emerging role of AKR1C3 to promote the stabilization of AR splice variant 7 (ARv7), 26 a major determinant of enzalutamide resistance, 27 further delineates its role as a central mediator of drug resistance in advanced PCa. 28 Thus, selective inhibition of AKR1C3 has emerged as a promising strategy for the discovery of potential therapeutics to directly treat PCa 29 and to counter AR antagonist drug resistance.…”

“…The enzyme is overexpressed at both the mRNA and protein levels in prostate tumors from castration-resistant prostate cancer (CRPC) patients but has low or undetectable expression in healthy prostate tissue. , Reduction of AKR1C3 expression or pharmacological inhibition significantly decreases the levels of T and DHT and androgen-dependent gene expression [prostate specific antigen (PSA)] . AKR1C3 has been shown to contribute to chemotherapeutic resistance in CRPC since its expression is increased in enzalutamide and abiraterone acetate-resistant PCa cell lines. − An emerging role of AKR1C3 to promote the stabilization of AR splice variant 7 (ARv7), a major determinant of enzalutamide resistance, further delineates its role as a central mediator of drug resistance in advanced PCa . Thus, selective inhibition of AKR1C3 has emerged as a promising strategy for the discovery of potential therapeutics to directly treat PCa and to counter AR antagonist drug resistance …”