title: ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer.
abstract: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors.
  
  
  
  AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model.
  
  
  
  We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression.
  
  
  
  ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. Clin Cancer Res; 22(14); 3672-82. ©2016 AACR.
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts. Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Huihui
authors.initials: H
authors.lastname: Ye
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sean
authors.initials: S
authors.lastname: Gerrin
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Akash
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam G
authors.initials: AG
authors.lastname: Sowalsky
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Olga
authors.initials: O
authors.lastname: Voznesensky
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
authors.forename: Wanting
authors.initials: W
authors.lastname: Han
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.affiliation: Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. changmeng.cai@umb.edu sbalk@bidmc.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts. Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. changmeng.cai@umb.edu sbalk@bidmc.harvard.edu.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
mesh_terms: D000728:Androgens / Q000235:genetics; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016729:Leuprolide / Q000494:pharmacology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011467:Prostate / Q000187:drug effects; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000728:Androgens; D000736:Androstenes; D016729:Leuprolide; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; C410798:AR protein, human; C508053:ERBB2 protein, human; C089740:abiraterone