title: A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509.
abstract: Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity due to a missense mutation (F876L) in the ligand-binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of castration-resistant prostate cancer (CRPC). Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509-treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of second-generation antiandrogen resistance that can potentially be targeted with next-generation antiandrogens.
  
  
  CONCLUSIONS
  A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509-treated patients with progressive disease. These results chart a new path for the discovery and development of next-generation antiandrogens that could be coupled with a blood-based companion diagnostic to guide treatment decisions.
authors.affiliation: Aragon Pharmaceuticals, Inc., San Diego, California.
authors.forename: James D
authors.initials: JD
authors.lastname: Joseph
authors.forename: Nhin
authors.initials: N
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: John
authors.initials: J
authors.lastname: Sensintaffar
authors.forename: Gang
authors.initials: G
authors.lastname: Shao
authors.forename: Dan
authors.initials: D
authors.lastname: Brigham
authors.forename: Michael
authors.initials: M
authors.lastname: Moon
authors.forename: Edna Chow
authors.initials: EC
authors.lastname: Maneval
authors.forename: Isan
authors.initials: I
authors.lastname: Chen
authors.forename: Beatrice
authors.initials: B
authors.lastname: Darimont
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D004247:DNA / Q000097:blood; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense / Q000235:genetics; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000235:genetics; D013867:Thiohydantoins / Q000627:therapeutic use*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D013867:Thiohydantoins; C572045:apalutamide; D010669:Phenylthiohydantoin; D004247:DNA; C540278:enzalutamide