title: Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer.
abstract: Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumor cells (CTC) to measure AR signaling readouts before and after therapeutic interventions. Single-cell immunofluorescence analysis revealed predominantly "AR-on" CTC signatures in untreated patients, compared with heterogeneous ("AR-on, AR-off, and AR-mixed") CTC populations in patients with CRPC. Initiation of first-line ADT induced a profound switch from "AR-on" to "AR-off" CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of "AR-mixed" CTCs and increasing "AR-on" cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer.
  
  
  CONCLUSIONS
  Acquired resistance to first-line hormonal therapy in prostate cancer is heterogeneous in the extent of AR pathway reactivation. Measurement of pre- and posttreatment AR signaling within CTCs may help target such treatments to patients most likely to respond to second-line therapies.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stott
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.forename: Matthew
authors.initials: M
authors.lastname: Ulman
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Smas
authors.forename: Jenna B
authors.initials: JB
authors.lastname: Lord
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.forename: Julie
authors.initials: J
authors.lastname: Trautwein
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D011944:Receptors, Androgen