Limits...
Persistent androgen receptor addiction in castration-resistant prostate cancer.

Schweizer MT, Yu EY - J Hematol Oncol (2015)

Bottom Line: While these drugs prolong survival in men with CRPC, they are unfortunately not curative.Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops.This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Department of Medicine, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. schweize@uw.edu.

ABSTRACT
It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling (e.g., AR amplification/overexpression, elucidations/concentration of intratumoral androgens), activation of the AR program via feedback pathways (e.g., AKT/mTOR/Pi3K, HER2/Neu), and activation of the AR program via mutation or substitution (e.g., AR ligand binding domain mutation; AR splice variants; glucocorticoid receptor signaling). This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

No MeSH data available.


Related in: MedlinePlus

Androgen Receptor Structure. a. The AR gene is located on the X chromosome at position Xq11-Xq12. It is composed of eight exons, which encode for four regions: N-terminal domain (NTD), DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD). b. Several cryptic exons (CE) as well as exon 9 are involved in the formation of several AR splice variants (AR-Vs) which lack the AR ligand binding domain. Four of these AR-Vs have been shown to possess constitutive activity (i.e., AR-V3, AR-V4, AR-V7, and AR-V12)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4644296&req=5

Fig1: Androgen Receptor Structure. a. The AR gene is located on the X chromosome at position Xq11-Xq12. It is composed of eight exons, which encode for four regions: N-terminal domain (NTD), DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD). b. Several cryptic exons (CE) as well as exon 9 are involved in the formation of several AR splice variants (AR-Vs) which lack the AR ligand binding domain. Four of these AR-Vs have been shown to possess constitutive activity (i.e., AR-V3, AR-V4, AR-V7, and AR-V12)

Mentions: The AR is a nuclear transcription factor encoded on the X chromosome at position Xq11-Xq12 [26, 27]. It contains eight exons and is composed of four domains: the N-terminal domain (i.e., transcriptional activation domain) (exon 1), DNA-binding domain (exons 2 and 3), a hinge region (exons 3 and 4), and the ligand-binding domain (i.e., C-terminal) (exons 4–8) (Fig. 1). An overly simplistic model of canonical AR signaling involves: (1) androgen binding the AR ligand binding domain, (2) dissociation of chaperone proteins (i.e., heat shock proteins), (3) AR nuclear transport and dimerization (likely through microtubule interaction with the hinge region), (4) binding of dimerized AR to androgen response elements (ARE) located within the promoters of AR target genes, (5) recruitment of AR co-activators, and (6) transcription of AR target genes. A number of additional events, such as AR phosphorylation and interaction with other co-regulators and transcription factors likely also play a role in modulating transcription of AR target genes [28].Fig. 1


Persistent androgen receptor addiction in castration-resistant prostate cancer.

Schweizer MT, Yu EY - J Hematol Oncol (2015)

Androgen Receptor Structure. a. The AR gene is located on the X chromosome at position Xq11-Xq12. It is composed of eight exons, which encode for four regions: N-terminal domain (NTD), DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD). b. Several cryptic exons (CE) as well as exon 9 are involved in the formation of several AR splice variants (AR-Vs) which lack the AR ligand binding domain. Four of these AR-Vs have been shown to possess constitutive activity (i.e., AR-V3, AR-V4, AR-V7, and AR-V12)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4644296&req=5

Fig1: Androgen Receptor Structure. a. The AR gene is located on the X chromosome at position Xq11-Xq12. It is composed of eight exons, which encode for four regions: N-terminal domain (NTD), DNA binding domain (DBD), the hinge region and the ligand binding domain (LBD). b. Several cryptic exons (CE) as well as exon 9 are involved in the formation of several AR splice variants (AR-Vs) which lack the AR ligand binding domain. Four of these AR-Vs have been shown to possess constitutive activity (i.e., AR-V3, AR-V4, AR-V7, and AR-V12)
Mentions: The AR is a nuclear transcription factor encoded on the X chromosome at position Xq11-Xq12 [26, 27]. It contains eight exons and is composed of four domains: the N-terminal domain (i.e., transcriptional activation domain) (exon 1), DNA-binding domain (exons 2 and 3), a hinge region (exons 3 and 4), and the ligand-binding domain (i.e., C-terminal) (exons 4–8) (Fig. 1). An overly simplistic model of canonical AR signaling involves: (1) androgen binding the AR ligand binding domain, (2) dissociation of chaperone proteins (i.e., heat shock proteins), (3) AR nuclear transport and dimerization (likely through microtubule interaction with the hinge region), (4) binding of dimerized AR to androgen response elements (ARE) located within the promoters of AR target genes, (5) recruitment of AR co-activators, and (6) transcription of AR target genes. A number of additional events, such as AR phosphorylation and interaction with other co-regulators and transcription factors likely also play a role in modulating transcription of AR target genes [28].Fig. 1

Bottom Line: While these drugs prolong survival in men with CRPC, they are unfortunately not curative.Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops.This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Department of Medicine, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. schweize@uw.edu.

ABSTRACT
It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling (e.g., AR amplification/overexpression, elucidations/concentration of intratumoral androgens), activation of the AR program via feedback pathways (e.g., AKT/mTOR/Pi3K, HER2/Neu), and activation of the AR program via mutation or substitution (e.g., AR ligand binding domain mutation; AR splice variants; glucocorticoid receptor signaling). This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.

No MeSH data available.


Related in: MedlinePlus