2. Academic Validation
  3. The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

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

  • Mol Cancer Ther. 2016 Jul;15(7):1702-12. doi: 10.1158/1535-7163.MCT-15-0892.
Stefan Prekovic 1,  Martin E van Royen 2,  Arnout R D Voet 3,  Bart Geverts 2,  Rene Houtman 4,  Diana Melchers 4,  Kam Y J Zhang 5,  Thomas Van den Broeck 6,  Elien Smeets 1,  Lien Spans 7,  Adriaan B Houtsmuller 8,  Steven Joniau 9,  Frank Claessens 10,  Christine Helsen 1
Affiliations

Affiliations

  • 1 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • 2 Department of Pathology, Erasmus MC, Rotterdam, the Netherlands.
  • 3 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.
  • 4 Pamgene International, the Netherlands.
  • 5 Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, Yokohama, Japan.
  • 6 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Department of Urology, University Hospitals Leuven, Leuven, Belgium.
  • 7 Laboratory for Genetics of Malignant Disorders, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 8 Department of Pathology, Erasmus MC, Rotterdam, the Netherlands. Erasmus Optical Imaging Center, Erasmus MC, Rotterdam, the Netherlands.
  • 9 Department of Urology, University Hospitals Leuven, Leuven, Belgium.
  • 10 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. frank.claessens@kuleuven.be.
PMID: 27196756 DOI: 10.1158/1535-7163.MCT-15-0892
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.

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