title: An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide).
abstract: Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR(F876L) confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK)4/6 inhibitors effectively antagonized AR(F876L) function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a "withdrawal" response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.
  
  
  CONCLUSIONS
  We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this fi nding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation.
authors.affiliation: 1Oncology Disease Area, 2Department of Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge; and 3Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Manav
authors.initials: M
authors.lastname: Korpal
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.forename: Xueliang
authors.initials: X
authors.lastname: Gao
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Rakiec
authors.forename: David A
authors.initials: DA
authors.lastname: Ruddy
authors.forename: Shivang
authors.initials: S
authors.lastname: Doshi
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.forename: Steve G
authors.initials: SG
authors.lastname: Kovats
authors.forename: Sunkyu
authors.initials: S
authors.lastname: Kim
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.forename: John E
authors.initials: JE
authors.lastname: Monahan
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Wenlai
authors.initials: W
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6