Loss of
Aged
Androgen Antagonists
/ administration & dosage
Androstenes
Anilides
Antineoplastic Agents, Hormonal
/ administration & dosage
Drug Resistance, Neoplasm
/ genetics
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Male
Nitriles
Oligopeptides
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Signal Transduction
Snail Family Transcription Factors
/ deficiency
Tosyl Compounds
Journal
JCO precision oncology
ISSN: 2473-4284
Titre abrégé: JCO Precis Oncol
Pays: United States
ID NLM: 101705370
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
20
08
2020
revised:
29
03
2021
accepted:
22
04
2021
entrez:
29
7
2021
pubmed:
30
7
2021
medline:
30
7
2021
Statut:
epublish
Résumé
Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for We show that EMT characterizes acutely resistant prostate tumors and that deletion of
Identifiants
pubmed: 34322653
doi: 10.1200/PO.20.00337
pii: PO.20.00337
pmc: PMC8238292
pii:
doi:
Substances chimiques
Androgen Antagonists
0
Androstenes
0
Anilides
0
Antineoplastic Agents, Hormonal
0
Nitriles
0
Oligopeptides
0
SNAI2 protein, human
0
Snail Family Transcription Factors
0
Tosyl Compounds
0
acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide
0
bicalutamide
A0Z3NAU9DP
abiraterone
G819A456D0
Banques de données
ANZCTR
['ACTRN12612000772842']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Informations de copyright
© 2021 by American Society of Clinical Oncology.
Déclaration de conflit d'intérêts
Geoff Macintyre Stock and Other Ownership Interests: Tailor Bio Ltd Uncompensated Relationships: Tailor Bio Ltd Jeremy Grummet Stock and Other Ownership Interests: MRI PRO Pty Ltd Honoraria: BK Ultrasound, Biobot, Mundipharma Travel, Accommodations, Expenses: Astellas Pharma Christopher M. Hovens Patents, Royalties, Other Intellectual Property: past patents in unrelated field Niall M. Corcoran Research Funding: Janssen Oncology No other potential conflicts of interest were reported.Geoff Macintyre Stock and Other Ownership Interests: Tailor Bio Ltd Uncompensated Relationships: Tailor Bio Ltd Jeremy Grummet Stock and Other Ownership Interests: MRI PRO Pty Ltd Honoraria: BK Ultrasound, Biobot, Mundipharma Travel, Accommodations, Expenses: Astellas Pharma Christopher M. Hovens Patents, Royalties, Other Intellectual Property: past patents in unrelated field Niall M. Corcoran Research Funding: Janssen Oncology No other potential conflicts of interest were reported.
Références
FASEB J. 2010 Mar;24(3):769-77
pubmed: 19901020
Prostate. 2011 Sep;71(12):1332-43
pubmed: 21321977
Cancer Res. 2008 Jun 1;68(11):4447-54
pubmed: 18519708
Cancer Discov. 2017 Nov;7(11):1248-1265
pubmed: 28864476
Cancer Res. 2012 Jan 15;72(2):527-36
pubmed: 22108827
Nat Med. 2004 Jan;10(1):33-9
pubmed: 14702632
Nature. 2012 Jul 12;487(7406):239-43
pubmed: 22722839
Oncotarget. 2015 Jul 10;6(19):17121-34
pubmed: 25686823
Cancer. 1992 Nov 1;70(9):2302-9
pubmed: 1382828
Br J Cancer. 2006 Jun 19;94(12):1816-22
pubmed: 16773075
Cell. 2013 Dec 5;155(6):1309-22
pubmed: 24315100
BMC Cancer. 2010 Jun 17;10:301
pubmed: 20565806
Cancer Cell. 2017 Aug 14;32(2):221-237.e13
pubmed: 28781121
J Clin Oncol. 2019 Apr 10;37(11):923-931
pubmed: 30811282
Eur Urol. 2019 Oct;76(4):418-424
pubmed: 31176622
BMC Cancer. 2010 Aug 06;10:411
pubmed: 20691079
BMC Cancer. 2012 Mar 19;12:91
pubmed: 22429801
Cell. 2017 Feb 9;168(4):613-628
pubmed: 28187284
Cancer Res. 2009 Jan 1;69(1):16-22
pubmed: 19117982
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13728-33
pubmed: 21795608
Cell. 2010 Apr 2;141(1):69-80
pubmed: 20371346
Control Clin Trials. 1989 Mar;10(1):1-10
pubmed: 2702835
Oncogene. 2012 Apr 19;31(16):2062-74
pubmed: 21874049
Cell. 2012 May 25;149(5):979-93
pubmed: 22608084
Cancer Res. 2018 Aug 15;78(16):4716-4730
pubmed: 29921690
Genome Biol. 2014 Aug 26;15(8):426
pubmed: 25155515
Int J Oncol. 2016 Aug;49(2):709-19
pubmed: 27277529
J Steroid Biochem Mol Biol. 1993 Dec;46(6):759-65
pubmed: 8274409
Nat Rev Cancer. 2015 Dec;15(12):701-11
pubmed: 26563462
Clin Cancer Res. 2005 Nov 15;11(22):8070-8
pubmed: 16299238
J Cell Biol. 1997 Jun 16;137(6):1403-19
pubmed: 9182671
Nat Methods. 2014 Apr;11(4):396-8
pubmed: 24633410
Oncogene. 2015 Aug 20;34(34):4448-59
pubmed: 25417704
J Clin Oncol. 2014 Nov 20;32(33):3705-15
pubmed: 25311217
Cell. 2013 Aug 29;154(5):1074-1084
pubmed: 23993097
Cell. 2005 Nov 18;123(4):641-53
pubmed: 16286009
J Urol. 2010 May;183(5):1808-14
pubmed: 20303103
Eur Urol. 2014 Jul;66(1):32-9
pubmed: 24054872
Clin Cancer Res. 2008 Jul 15;14(14):4622-30
pubmed: 18628477
Mol Cell Biol. 2012 Mar;32(5):941-53
pubmed: 22203039
Nat Rev Cancer. 2013 Oct;13(10):714-26
pubmed: 24060863
Pathology. 2012 Apr;44(3):204-8
pubmed: 22406482
Science. 2020 May 1;368(6490):497-505
pubmed: 32355025
Nature. 2018 Apr;556(7702):463-468
pubmed: 29670281
Eur Urol. 2017 Feb;71(2):183-192
pubmed: 27451135
N Engl J Med. 2014 Sep 11;371(11):1028-38
pubmed: 25184630
Cancer Res. 2016 Nov 15;76(22):6520-6532
pubmed: 27651311
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
J Clin Oncol. 2014 Jan 20;32(3):229-37
pubmed: 24323034
Nat Rev Urol. 2017 Jan;14(1):49-58
pubmed: 27824348
Tumour Biol. 2010 Aug;31(4):297-307
pubmed: 20506051
Cancer Lett. 2015 Dec 1;369(1):103-11
pubmed: 26297988
Am J Respir Crit Care Med. 2011 Apr 15;183(8):1071-9
pubmed: 21037017
Stem Cells. 2009 Sep;27(9):2059-68
pubmed: 19544473
J Cell Sci. 2019 Dec 2;132(23):
pubmed: 31792043
Clin Cancer Res. 2014 Nov 1;20(21):5547-57
pubmed: 24771644
Nature. 2017 Jun 15;546(7658):431-435
pubmed: 28607484