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

Stefan Prekovic; Martin E van Royen; Arnout R D Voet; Bart Geverts; Rene Houtman; Diana Melchers; Kam Y J Zhang; Thomas Van den Broeck; Elien Smeets; Lien Spans; Adriaan B Houtsmuller; Steven Joniau; Frank Claessens; Christine Helsen

doi:10.1158/1535-7163.MCT-15-0892

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

Stefan Prekovic, Martin E van Royen, Arnout R D Voet, Bart Geverts, Rene Houtman, Diana Melchers, Kam Y J Zhang, Thomas Van den Broeck, Elien Smeets, Lien Spans, Adriaan B Houtsmuller, Steven Joniau, Frank Claessens, Christine Helsen

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1702-12
Number of pages	11
Journal	MOLECULAR CANCER THERAPEUTICS
Volume	15
Issue number	7
DOIs	https://doi.org/10.1158/1535-7163.MCT-15-0892
Publication status	Published - Jul 2016
Externally published	Yes

Keywords

Amino Acid Substitution
Androgen Antagonists/pharmacology
Antineoplastic Agents/chemistry
Benzamides
Cell Line, Tumor
Cluster Analysis
Codon
Drug Resistance, Neoplasm/genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Ligands
Models, Molecular
Molecular Conformation
Mutation
Nitriles
Phenylthiohydantoin/analogs & derivatives
Protein Binding
Receptors, Androgen/chemistry
Structure-Activity Relationship
Transcriptional Activation

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10.1158/1535-7163.MCT-15-0892

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Prekovic, S., van Royen, M. E., Voet, A. R. D., Geverts, B., Houtman, R., Melchers, D., Zhang, K. Y. J., Van den Broeck, T., Smeets, E., Spans, L., Houtsmuller, A. B., Joniau, S., Claessens, F., & Helsen, C. (2016). The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide. MOLECULAR CANCER THERAPEUTICS, 15(7), 1702-12. https://doi.org/10.1158/1535-7163.MCT-15-0892

@article{7cf40b09ec54450ea8d11a67edbaf323,

title = "The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide",

abstract = "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. {\textcopyright}2016 AACR.",

keywords = "Amino Acid Substitution, Androgen Antagonists/pharmacology, Antineoplastic Agents/chemistry, Benzamides, Cell Line, Tumor, Cluster Analysis, Codon, Drug Resistance, Neoplasm/genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Ligands, Models, Molecular, Molecular Conformation, Mutation, Nitriles, Phenylthiohydantoin/analogs \& derivatives, Protein Binding, Receptors, Androgen/chemistry, Structure-Activity Relationship, Transcriptional Activation",

author = "Stefan Prekovic and \{van Royen\}, \{Martin E\} and Voet, \{Arnout R D\} and Bart Geverts and Rene Houtman and Diana Melchers and Zhang, \{Kam Y J\} and \{Van den Broeck\}, Thomas and Elien Smeets and Lien Spans and Houtsmuller, \{Adriaan B\} and Steven Joniau and Frank Claessens and Christine Helsen",

note = "{\textcopyright}2016 American Association for Cancer Research.",

year = "2016",

month = jul,

doi = "10.1158/1535-7163.MCT-15-0892",

language = "English",

volume = "15",

pages = "1702--12",

journal = "MOLECULAR CANCER THERAPEUTICS",

issn = "1535-7163",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

Prekovic, S, van Royen, ME, Voet, ARD, Geverts, B, Houtman, R, Melchers, D, Zhang, KYJ, Van den Broeck, T, Smeets, E, Spans, L, Houtsmuller, AB, Joniau, S, Claessens, F & Helsen, C 2016, 'The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide', MOLECULAR CANCER THERAPEUTICS, vol. 15, no. 7, pp. 1702-12. https://doi.org/10.1158/1535-7163.MCT-15-0892

TY - JOUR

T1 - The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

AU - Prekovic, Stefan

AU - van Royen, Martin E

AU - Voet, Arnout R D

AU - Geverts, Bart

AU - Houtman, Rene

AU - Melchers, Diana

AU - Zhang, Kam Y J

AU - Van den Broeck, Thomas

AU - Smeets, Elien

AU - Spans, Lien

AU - Houtsmuller, Adriaan B

AU - Joniau, Steven

AU - Claessens, Frank

AU - Helsen, Christine

PY - 2016/7

Y1 - 2016/7

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - Androgen Antagonists/pharmacology

KW - Antineoplastic Agents/chemistry

KW - Benzamides

KW - Cell Line, Tumor

KW - Cluster Analysis

KW - Codon

KW - Drug Resistance, Neoplasm/genetics

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Molecular Conformation

KW - Mutation

KW - Nitriles

KW - Phenylthiohydantoin/analogs & derivatives

KW - Protein Binding

KW - Receptors, Androgen/chemistry

KW - Structure-Activity Relationship

KW - Transcriptional Activation

U2 - 10.1158/1535-7163.MCT-15-0892

DO - 10.1158/1535-7163.MCT-15-0892

M3 - Article

C2 - 27196756

SN - 1535-7163

VL - 15

SP - 1702

EP - 1712

JO - MOLECULAR CANCER THERAPEUTICS

JF - MOLECULAR CANCER THERAPEUTICS

IS - 7

ER -

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

Abstract

Keywords

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