title: A novel nonsense mutation in androgen receptor confers resistance to CYP17 inhibitor treatment in prostate cancer.
abstract: The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again. Importantly, AR mutations are more frequently detected in this type of cancer. By analyzing tumor biopsy mRNA from CRPC patients who had developed resistance to CYP17 inhibitor treatment, we have identified a novel nonsense mutation (Q784*) at the ligand binding domain (LBD) of AR, which produces a C-terminal truncated AR protein that lacks intact LBD. This AR-Q784* mutant is transcriptionally inactive, but it is constitutively expressed in the nucleus and can bind to DNA in the absence of androgen. Significantly, our results show that AR-Q784* can heterodimerize with, and enhance the transcriptional activity of, full-length AR. Moreover, expressing AR-Q784* in an AR positive PCa cell line enhances the chromatin binding of endogenous AR and the recruitment of p300 coactivator under the low androgen condition, leading to increased cell growth. This activity of AR-Q784* mimics the function of some AR splice variants, indicating that CYP17 inhibitor treatment in CRPC may select for LBD-truncated forms of AR to restore AR signaling.
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.|Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Valencia
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.
authors.forename: Jude
authors.initials: J
authors.lastname: Owiredu
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.
authors.forename: Wanting
authors.initials: W
authors.lastname: Han
authors.affiliation: Biology Department, University of Suffolk, Boston, Massachusetts 02108, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: de Waal
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Macoska
authors.affiliation: Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts 02125, USA.|Hematology-Oncology Division and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Changmeng
authors.initials: C
authors.lastname: Cai
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D018389:Codon, Nonsense; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068538:Dutasteride / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D016896:Treatment Outcome; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; C410798:AR protein, human; D002843:Chromatin; D018389:Codon, Nonsense; D065607:Cytochrome P-450 Enzyme Inhibitors; D011944:Receptors, Androgen; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D050880:p300-CBP Transcription Factors; D000068538:Dutasteride; D007654:Ketoconazole
keywords: CYP17 inhibitor; abiraterone; androgen receptor; androgen receptor mutation; prostate cancer