The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells...

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Veröffentlicht in:Molecular cancer therapeutics 2016-07, Vol.15 (7), p.1702-1712
Hauptverfasser: Prekovic, Stefan, van Royen, Martin E, Voet, Arnout R D, Geverts, Bart, Houtman, Rene, Melchers, Diana, Zhang, Kam Y J, Van den Broeck, Thomas, Smeets, Elien, Spans, Lien, Houtsmuller, Adriaan B, Joniau, Steven, Claessens, Frank, Helsen, Christine
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container_end_page 1712
container_issue 7
container_start_page 1702
container_title Molecular cancer therapeutics
container_volume 15
creator Prekovic, Stefan
van Royen, Martin E
Voet, Arnout R D
Geverts, Bart
Houtman, Rene
Melchers, Diana
Zhang, Kam Y J
Van den Broeck, Thomas
Smeets, Elien
Spans, Lien
Houtsmuller, Adriaan B
Joniau, Steven
Claessens, Frank
Helsen, Christine
description Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR. Mol Cancer Ther; 15(7); 1702-12. ©2016 AACR.
doi_str_mv 10.1158/1535-7163.MCT-15-0892
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Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR. 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source MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals
subjects Amino Acid Substitution
Androgen Antagonists - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cluster Analysis
Codon
Drug Resistance, Neoplasm - genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Ligands
Models, Molecular
Molecular Conformation
Mutation
Phenylthiohydantoin - analogs & derivatives
Phenylthiohydantoin - chemistry
Phenylthiohydantoin - pharmacology
Protein Binding
Receptors, Androgen - chemistry
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Structure-Activity Relationship
Transcriptional Activation
title The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide
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