Assessment of Androgen Receptor Splice Variant-7 as a Biomarker of Clinical Response in Castration-Sensitive Prostate Cancer.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 08 2022
15 08 2022
Historique:
received:
16
03
2022
revised:
17
05
2022
accepted:
08
06
2022
pubmed:
14
6
2022
medline:
17
8
2022
entrez:
13
6
2022
Statut:
ppublish
Résumé
Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance in CSPC remains understudied. We assessed different approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines, patient-derived xenograft (PDX) models, publicly available cohorts, and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein and its association with clinical outcome. In CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts but rarely identified AR-V7 protein reactivity in CSPC cohorts, when compared with the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC institutional cohorts, AR-V7 protein quantification by either assay was associated neither with time to development of castration resistance nor with overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant AR-V7 mRNA or staining following treatment. Neither pre- nor posttreatment AR-V7 levels were associated with volumes of residual disease after therapy. This study demonstrates that further analytical validation and clinical qualification are required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
Identifiants
pubmed: 35695870
pii: 707390
doi: 10.1158/1078-0432.CCR-22-0851
pmc: PMC9378683
mid: NIHMS1817508
doi:
Substances chimiques
Androgen Antagonists
0
Biomarkers
0
Protein Isoforms
0
RNA, Messenger
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3509-3525Subventions
Organisme : Medical Research Council
ID : MR/M018318/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA090381
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234715
Pays : United States
Organisme : Medical Research Council
ID : MR/W018217/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011679
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011838
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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