Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.
HRD
RAD51
immune exclusion
multiplexed IHC
ovarian cancer
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 05 2021
07 05 2021
Historique:
revised:
04
02
2021
received:
02
09
2020
accepted:
09
02
2021
pubmed:
13
3
2021
medline:
26
10
2021
entrez:
12
3
2021
Statut:
ppublish
Résumé
Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
Identifiants
pubmed: 33709473
doi: 10.15252/emmm.202013366
pmc: PMC8103098
doi:
Substances chimiques
Platinum
49DFR088MY
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
Paclitaxel
P88XT4IS4D
Banques de données
GEO
['GSE166539', 'GSE3149', 'GSE26712', 'GSE9891']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13366Subventions
Organisme : Cancer Research UK
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Oncotarget. 2015 Dec 22;6(41):43843-52
pubmed: 26549805
Nature. 2006 Jan 19;439(7074):353-7
pubmed: 16273092
N Engl J Med. 2016 Dec;375(22):2154-2164
pubmed: 27717299
J Natl Cancer Inst. 2018 Aug 1;110(8):803-811
pubmed: 29873743
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6236-40
pubmed: 8692798
Histopathology. 2009 Dec;55(6):696-704
pubmed: 20002770
Nat Commun. 2013;4:2126
pubmed: 23839242
Ann Oncol. 2013 Mar;24(3):679-87
pubmed: 23041585
J Clin Invest. 2018 Oct 1;128(10):4236-4242
pubmed: 30272580
Clin Cancer Res. 2008 Aug 15;14(16):5198-208
pubmed: 18698038
Breast Cancer Res Treat. 2016 Aug;159(1):41-53
pubmed: 27464795
Ann Oncol. 2019 May 1;30(5):672-705
pubmed: 31046081
Nat Commun. 2017 Oct 16;8(1):859
pubmed: 29038466
Clin Cancer Res. 2007 Jul 1;13(13):3942-50
pubmed: 17606728
Nucleic Acids Res. 2017 May 5;45(8):4590-4605
pubmed: 28334891
Cancer Res. 2008 Jul 1;68(13):5478-86
pubmed: 18593951
EMBO Mol Med. 2021 May 7;13(5):e13366
pubmed: 33709473
Int J Cancer. 2013 May 1;132(9):2118-26
pubmed: 23065657
Nat Commun. 2019 Sep 27;10(1):4410
pubmed: 31562309
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Clin Cancer Res. 2016 Aug 1;22(15):3764-73
pubmed: 26957554
Cancers (Basel). 2020 Jun 17;12(6):
pubmed: 32560564
Mol Cancer Res. 2018 Jul;16(7):1103-1111
pubmed: 29724815
EMBO J. 1998 Jan 15;17(2):598-608
pubmed: 9430650
Mol Cell Biol. 2000 Nov;20(21):7980-90
pubmed: 11027268
Nat Protoc. 2012 Sep;7(9):1755-64
pubmed: 22936217
EMBO J. 2006 Mar 22;25(6):1285-94
pubmed: 16482220
Br J Cancer. 2005 Jul 11;93(1):137-43
pubmed: 15956972
Lung Cancer. 2020 Sep;147:30-38
pubmed: 32653671
Mol Oncol. 2014 May;8(3):656-68
pubmed: 24560445
Gynecol Oncol. 2014 Jun;133(3):624-31
pubmed: 24607285
Clin Cancer Res. 2018 Sep 15;24(18):4482-4493
pubmed: 29858219
J Clin Oncol. 1991 Mar;9(3):389-93
pubmed: 1999708
Nucleic Acids Res. 2016 Jul 27;44(13):6070-86
pubmed: 27280975
Clin Cancer Res. 2010 Dec 15;16(24):6159-68
pubmed: 20802015
PLoS Biol. 2020 Jul 14;18(7):e3000410
pubmed: 32663219
Clin Cancer Res. 2014 Sep 15;20(18):4816-26
pubmed: 24963051
EMBO Mol Med. 2018 Dec;10(12):
pubmed: 30377213
Nat Commun. 2016 Aug 30;7:12624
pubmed: 27571927
J Clin Oncol. 2008 Dec 1;26(34):5530-6
pubmed: 18955455
Int J Mol Sci. 2020 May 28;21(11):
pubmed: 32481589