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

S Prekovic, Martin van Royen, ARD Voet, B (Bart) Geverts, R Houtman, D Melchers, KYJ Zhang, T Van Den Broeck, E Smeets, L Spans, Adriaan Houtsmuller, S Joniau, F Claessens, C Helsen

Research output: Contribution to journalArticleAcademicpeer-review

75 Citations (Scopus)


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. (C) 2016 AACR.
Original languageUndefined/Unknown
Pages (from-to)1702-1712
Number of pages11
JournalMolecular Cancer Therapeutics
Issue number7
Publication statusPublished - 2016

Research programs

  • EMC MM-03-24-01

Cite this