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. ©2016 AACR.
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prekovic
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Martin E
authors.initials: ME
authors.lastname: van Royen
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, Yokohama, Japan. Laboratory for Biomolecular Modeling and Design, Department of Chemistry, KU Leuven, Leuven, Belgium.
authors.forename: Arnout R D
authors.initials: AR
authors.lastname: Voet
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Geverts
authors.affiliation: Pamgene International, the Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Houtman
authors.affiliation: Pamgene International, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Melchers
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, Yokohama, Japan.
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Department of Urology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Van den Broeck
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Elien
authors.initials: E
authors.lastname: Smeets
authors.affiliation: Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Spans
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, the Netherlands. Erasmus Optical Imaging Center, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Adriaan B
authors.initials: AB
authors.lastname: Houtsmuller
authors.affiliation: Department of Urology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. frank.claessens@kuleuven.be.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
authors.affiliation: Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Helsen
mesh_terms: D019943:Amino Acid Substitution; D000726:Androgen Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003062:Codon; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D003062:Codon; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide