title: Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors.
abstract: OBJECTIVE
  The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.
  
  
  METHODS
  AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
  
  
  RESULTS
  The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.
  
  
  CONCLUSIONS
  These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eddy J
authors.initials: EJ
authors.lastname: Chen
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Olga
authors.initials: O
authors.lastname: Voznesensky
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schaefer
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Huihui
authors.initials: H
authors.lastname: Ye
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rosina L
authors.initials: RL
authors.lastname: Lis
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: University of Washington, Seattle, Washington.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Montgomery
authors.affiliation: University of Washington, Seattle, Washington. Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. sbalk@bidmc.harvard.edu mary_taplin@dfci.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. sbalk@bidmc.harvard.edu mary_taplin@dfci.harvard.edu.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000068538:Dutasteride / Q000627:therapeutic use; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use; D016729:Leuprolide / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011374:Progesterone / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*
chemical_list: D000736:Androstenes; D004268:DNA-Binding Proteins; D011944:Receptors, Androgen; D011374:Progesterone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D004265:DNA Helicases; C080359:CHD1 protein, human; D016729:Leuprolide; C089740:abiraterone; D000068538:Dutasteride; D007654:Ketoconazole