Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.
Animals
Antibodies, Monoclonal
/ pharmacology
Base Sequence
Benzopyrans
/ pharmacology
Carcinoma, Ovarian Epithelial
/ genetics
Cell Line, Tumor
Endoplasmic Reticulum Stress
/ drug effects
Endoribonucleases
/ antagonists & inhibitors
Female
Gene Expression Regulation, Neoplastic
Humans
Hymecromone
/ analogs & derivatives
Immune Checkpoint Inhibitors
Mice
Molecular Targeted Therapy
Ovarian Neoplasms
/ genetics
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Protein Binding
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Protein-Arginine N-Methyltransferases
/ antagonists & inhibitors
Signal Transduction
X-Box Binding Protein 1
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 09 2021
07 09 2021
Historique:
received:
19
11
2020
accepted:
25
08
2021
entrez:
8
9
2021
pubmed:
9
9
2021
medline:
7
10
2021
Statut:
epublish
Résumé
CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.
Identifiants
pubmed: 34493732
doi: 10.1038/s41467-021-25684-3
pii: 10.1038/s41467-021-25684-3
pmc: PMC8423755
doi:
Substances chimiques
4-methylumbelliferone 8-carbaldehyde
0
Antibodies, Monoclonal
0
Benzopyrans
0
Immune Checkpoint Inhibitors
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
X-Box Binding Protein 1
0
XBP1 protein, human
0
Hymecromone
3T5NG4Q468
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
coactivator-associated arginine methyltransferase 1
EC 2.1.1.319
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5321Subventions
Organisme : NCI NIH HHS
ID : K99 CA241395
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163910
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA241395
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG031862
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA228991
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202919
Pays : United States
Organisme : NINDS NIH HHS
ID : K23 NS105575
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239128
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA247336
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA160331
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163377
Pays : United States
Organisme : NINDS NIH HHS
ID : DP2 NS105576
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190860
Pays : United States
Informations de copyright
© 2021. The Author(s).
Références
Cancer. 2004 Jul 1;101(1):83-9
pubmed: 15221992
Bioinformatics. 2010 Sep 1;26(17):2204-7
pubmed: 20639541
Trends Cancer. 2016 May;2(5):252-262
pubmed: 28741511
Nat Cell Biol. 2017 Jun;19(6):698-710
pubmed: 28459443
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
J Clin Invest. 2014 Jun;124(6):2585-98
pubmed: 24812669
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Cancer Immunol Res. 2018 Jun;6(6):696-710
pubmed: 29650518
Trends Immunol. 2019 Feb;40(2):128-141
pubmed: 30612925
Cell. 2017 Feb 9;168(4):692-706
pubmed: 28187289
Nat Commun. 2018 Feb 12;9(1):631
pubmed: 29434212
Elife. 2017 Jan 16;6:
pubmed: 28079019
Cancer Cell. 2020 Feb 10;37(2):157-167.e6
pubmed: 32004442
Methods Mol Biol. 2009;543:253-66
pubmed: 19378171
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nature. 2015 Jan 29;517(7536):583-8
pubmed: 25494202
Sci Adv. 2019 May 22;5(5):eaaw5294
pubmed: 31131328
Nat Methods. 2016 Jun;13(6):521-7
pubmed: 27135972
Cancer Chemother Pharmacol. 1989;24(3):181-6
pubmed: 2736709
Nat Chem Biol. 2020 Nov;16(11):1152
pubmed: 33067597
Genome Biol. 2014;15(12):550
pubmed: 25516281
J Clin Invest. 2018 Apr 2;128(4):1300-1316
pubmed: 29381485
Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13351-6
pubmed: 16938873
Nat Rev Cancer. 2015 Nov;15(11):668-79
pubmed: 26493647
BMC Cancer. 2010 May 13;10:197
pubmed: 20462455
Cancer Res. 2019 Dec 15;79(24):6190-6203
pubmed: 31672843
Annu Rev Pathol. 2009;4:287-313
pubmed: 18842102
Nat Chem Biol. 2019 Aug;15(8):764-775
pubmed: 31320759
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Nat Rev Cancer. 2013 Jan;13(1):37-50
pubmed: 23235912
Nature. 2014 Apr 3;508(7494):103-107
pubmed: 24670641
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Cell Death Differ. 2004 Apr;11(4):381-9
pubmed: 14685163
Sci Immunol. 2016 Aug;1(2):
pubmed: 28417112
Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5675-80
pubmed: 22451921
J Exp Med. 2012 Mar 12;209(3):495-506
pubmed: 22351930
Cancer Cell. 2014 Jan 13;25(1):21-36
pubmed: 24434208