title: Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants.
abstract: OBJECTIVE
  Abiraterone is a potent inhibitor of the steroidogenic enzyme CYP17A1 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The effectiveness of abiraterone in reducing tumor androgens is not known, nor have mechanisms contributing to abiraterone resistance been established.
  
  
  METHODS
  We treated human CRPC xenografts with abiraterone and measured tumor growth, tissue androgens, androgen receptor (AR) levels, and steroidogenic gene expression versus controls.
  
  
  RESULTS
  Abiraterone suppressed serum PSA levels and improved survival in two distinct CRPC xenografts: median survival of LuCaP35CR improved from 17 to 39 days (HR = 3.6, P = 0.0014) and LuCaP23CR from 14 to 24 days (HR = 2.5, P = 0.0048). Abiraterone strongly suppressed tumor androgens, with testosterone (T) decreasing from 0.49 ± 0.22 to 0.03 ± 0.01 pg/mg (P < 0.0001), and from 0.69 ± 0.36 to 0.03 ± 0.01 pg/mg (P = 0.002) in abiraterone-treated 23CR and 35CR, respectively, with comparable decreases in tissue DHT. Treatment was associated with increased expression of full-length AR (AR(FL)) and truncated AR variants (AR(FL) 2.3-fold, P = 0.008 and AR(del567es) 2.7-fold, P = 0.036 in 23 CR; AR(FL) 3.4-fold, P = 0.001 and AR(V7) 3.1-fold, P = 0.0003 in 35CR), and increased expression of the abiraterone target CYP17A1 (∼2.1-fold, P = 0.0001 and P = 0.028 in 23CR and 35CR, respectively) and transcript changes in other enzymes modulating steroid metabolism.
  
  
  CONCLUSIONS
  These studies indicate that abiraterone reduces CRPC growth via suppression of intratumoral androgens and that resistance to abiraterone may occur through mechanisms that include upregulation of CYP17A1, and/or induction of AR and AR splice variants that confer ligand-independent AR transactivation.
authors.affiliation: Division of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington, Seattle, Washington, USA. emostagh@fhcrc.org
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.forename: Brett T
authors.initials: BT
authors.lastname: Marck
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Stephen
authors.initials: S
authors.lastname: Balk
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Matsumoto
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Montgomery
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000728:Androgens / Q000378:metabolism; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D053898:Biosynthetic Pathways / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011944:Receptors, Androgen / Q000235:genetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone