Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2–3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR‑dependent and contribute to PCa drug resistance will be discussed.

Download Full-text

SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

Scientific Reports ◽

10.1038/s41598-021-93971-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Diana Trnski ◽

Maja Sabol ◽

Sanja Tomić ◽

Ivan Štefanac ◽

Milanka Mrčela ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Therapy Resistance ◽

Androgen Deprivation ◽

Prostate Cancer Cells ◽

Androgen Independence ◽

Androgen Receptor Activity ◽

Signaling Activation ◽

Androgen Independent

AbstractProstate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

Download Full-text

Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽

10.3390/cancers13163959 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3959

Author(s):

Oluwaseun Adebayo Bamodu ◽

Yuan-Hung Wang ◽

Chen-Hsun Ho ◽

Su-Wei Hu ◽

Chia-Da Lin ◽

...

Keyword(s):

Prostate Cancer ◽

Disease Progression ◽

Therapy Resistance ◽

Calcium Signal ◽

Signal Transducer ◽

Castration Resistance ◽

Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Download Full-text

Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

Cancers ◽

10.3390/cancers13133272 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3272

Author(s):

Lauren K. Jillson ◽

Gabriel A. Yette ◽

Teemu D. Laajala ◽

Wayne D. Tilley ◽

James C. Costello ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Targeted Therapies ◽

Meta Analysis ◽

Therapy Resistance ◽

Androgen Receptor Signaling ◽

Genomic Changes ◽

Risk Patients ◽

Important Pathway ◽

Therapy Option

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.

Download Full-text

MP24-06 INTERACTION BETWEEN DOCETAXEL RESISTANCE AND CASTRATION RESISTANCE IN PROSTATE CANCER: IMPLICATIONS OF TWIST1, YB-1 AND ANDROGEN RECEPTOR

The Journal of Urology ◽

10.1016/j.juro.2014.02.287 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

Masaki Shiota ◽

Eiji Kashiwagi ◽

Akira Yokomizo ◽

Ario Takeuchi ◽

Takeshi Dejima ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Castration Resistance ◽

Docetaxel Resistance

Download Full-text

Selective degradation of AR-V7 to overcome castration resistance of prostate cancer

Cell Death and Disease ◽

10.1038/s41419-021-04162-0 ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Yuan Liu ◽

Cuifu Yu ◽

Zhenlong Shao ◽

Xiaohong Xia ◽

Tumei Hu ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Selective Inhibition ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Selective Degradation ◽

Castration Resistant ◽

Novel Drugs ◽

The Stability ◽

Androgen Receptor Splice Variant

AbstractAndrogen receptor splice variant 7 (AR-V7), a form of ligand-independent and constitutively activating variant of androgen receptor (AR), is considered as the key driver to initiate castration-resistant prostate cancer (CRPC). Because AR-V7 lacks ligand-binding domain, the AR-targeted therapies that aim to inactivate AR signaling through disrupting the interaction between AR and androgen are limited in CRPC. Thus, the emergence of AR-V7 has become the greatest challenge for treating CRPC. Targeting protein degradation is a recently proposed novel avenue for cancer treatment. Our previous studies have been shown that the oncoprotein AR-V7 is a substrate of the proteasome. Identifying novel drugs that can trigger the degradation of AR-V7 is therefore critical to cure CRPC. Here we show that nobiletin, a polymethoxylated flavonoid derived from the peel of Citrus fruits, exerts a potent anticancer activity via inducing G0/G1 phase arrest and enhancing the sensitivity of cells to enzalutamide in AR-V7 positive PC cells. Mechanically, we unravel that nobiletin selectively induces proteasomal degradation of AR-V7 (but not AR). This effect relies on its selective inhibition of the interactions between AR-V7 and two deubiquitinases USP14 and USP22. These findings not only enrich our understanding on the mechanism of AR-V7 degradation, but also provide an efficient and druggable target for overcoming CRPC through interfering the stability of AR-V7 mediated by the interaction between AR-V7 and deubiquitinase.

Download Full-text

Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

Cancers ◽

10.3390/cancers9060067 ◽

2017 ◽

Vol 9 (12) ◽

pp. 67 ◽

Cited By ~ 27

Author(s):

Daniel Crona ◽

Young Whang

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Therapy ◽

Therapy Resistance ◽

Prostate Cancer Therapy

Download Full-text

Long noncoding RNA CRAT1 inhibits castration-resistance of prostate cancer via inhibiting androgen receptor protein translation

European Urology Supplements ◽

10.1016/s1569-9056(19)30049-1 ◽

2019 ◽

Vol 18 (1) ◽

pp. e65

Author(s):

C. Xu ◽

G. Peng ◽

X. Ruihui ◽

H. Ming ◽

Z. Qianghua ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Protein Translation ◽

Receptor Protein ◽

Castration Resistance ◽

Androgen Receptor Protein

Download Full-text

Cell-Free DNA Alterations in the AR Enhancer and Locus Predict Resistance to AR-Directed Therapy in Patients With Metastatic Prostate Cancer

JCO Precision Oncology ◽

10.1200/po.20.00047 ◽

2020 ◽

pp. 680-713 ◽

Cited By ~ 1

Author(s):

Ha X. Dang ◽

Pradeep S. Chauhan ◽

Haley Ellis ◽

Wenjia Feng ◽

Peter K. Harris ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Metastatic Prostate Cancer ◽

Progression Free Survival ◽

Therapy Resistance ◽

Cancer Resistance ◽

Liquid Biopsies ◽

Genomic Alterations ◽

Cell Free Dna ◽

Free Dna

PURPOSE Cell-free DNA (cfDNA) and circulating tumor cell (CTC)–based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)–directed therapy in metastatic prostate cancer. However, because of complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (eg, CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in > 80% of patients with metastatic disease and its association with disease resistance presents an opportunity to improve on current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. PATIENTS AND METHODS We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). RESULTS EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS, 30% v 71%; P = .0002; 6-month OS, 59% v 100%; P = .0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay, which was also run on a subset of patients. CONCLUSION cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.

Download Full-text