Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.
BAP1
EZH2
Polycomb
combination therapy
mesothelioma
mevalonate
preclinical models
targeted therapy
uveal melanoma
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
21 02 2023
21 02 2023
Historique:
received:
29
06
2022
revised:
06
12
2022
accepted:
30
12
2022
pubmed:
20
1
2023
medline:
25
2
2023
entrez:
19
1
2023
Statut:
ppublish
Résumé
More than half of patients with malignant mesothelioma show alterations in the BAP1 tumor-suppressor gene. Being a member of the Polycomb repressive deubiquitinating (PR-DUB) complex, BAP1 loss results in an altered epigenome, which may create new vulnerabilities that remain largely unknown. Here, we performed a CRISPR-Cas9 kinome screen in mesothelioma cells that identified two kinases in the mevalonate/cholesterol biosynthesis pathway. Furthermore, our analysis of chromatin, expression, and genetic perturbation data in mesothelioma cells suggests a dependency on PR complex 2 (PRC2)-mediated silencing. Pharmacological inhibition of PRC2 elevates the expression of cholesterol biosynthesis genes only in BAP1-deficient mesothelioma, thereby sensitizing these cells to the combined targeting of PRC2 and the mevalonate pathway. Finally, by subjecting autochthonous Bap1-deficient mesothelioma mice or xenografts to mevalonate pathway inhibition (zoledronic acid) and PRC2 inhibition (tazemetostat), we demonstrate a potent anti-tumor effect, suggesting a targeted combination therapy for Bap1-deficient mesothelioma.
Identifiants
pubmed: 36657447
pii: S2666-3791(22)00494-3
doi: 10.1016/j.xcrm.2022.100915
pmc: PMC9975229
pii:
doi:
Substances chimiques
Mevalonic Acid
S5UOB36OCZ
Tumor Suppressor Proteins
0
Cholesterol
97C5T2UQ7J
Ubiquitin Thiolesterase
EC 3.4.19.12
BAP1 protein, human
0
BAP1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100915Subventions
Organisme : Medical Research Council
ID : MR/M015831/1
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
J Exp Med. 2020 Jun 1;217(6):
pubmed: 32271879
Nat Rev Cancer. 2017 Jul 25;17(8):475-488
pubmed: 28740119
Nat Biotechnol. 2016 Feb;34(2):184-191
pubmed: 26780180
Nat Rev Drug Discov. 2020 Jan;19(1):23-38
pubmed: 31712683
Lancet Oncol. 2022 Jun;23(6):758-767
pubmed: 35588752
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Carcinogenesis. 2013 Jul;34(7):1413-9
pubmed: 23677068
Science. 2010 Dec 3;330(6009):1410-3
pubmed: 21051595
Lancet. 2012 Jul 28;380(9839):358-65
pubmed: 22735384
J Thorac Oncol. 2015 Nov;10(11):1634-41
pubmed: 26317916
Nat Med. 2015 Nov;21(11):1344-9
pubmed: 26437366
J Transl Med. 2012 Aug 30;10:179
pubmed: 22935333
Cell Rep. 2015 Mar 3;10(8):1422-32
pubmed: 25732831
Lancet. 2021 Jan 30;397(10272):375-386
pubmed: 33485464
Mol Oncol. 2014 Sep 12;8(6):1067-83
pubmed: 24910388
J Thorac Oncol. 2015 Apr;10(4):565-76
pubmed: 25658628
Front Oncol. 2021 Feb 25;11:626971
pubmed: 33718197
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nature. 2019 Nov;575(7782):299-309
pubmed: 31723286
J Thorac Oncol. 2012 Sep;7(9):1449-56
pubmed: 22895142
Nat Commun. 2021 Sep 13;12(1):5402
pubmed: 34518527
Cancers (Basel). 2021 Mar 30;13(7):
pubmed: 33808217
Ther Clin Risk Manag. 2008 Feb;4(1):261-8
pubmed: 18728715
Cell Rep. 2016 Jul 12;16(2):583-595
pubmed: 27373151
Nat Genet. 2016 Apr;48(4):407-16
pubmed: 26928227
Nat Biotechnol. 2014 Sep;32(9):941-6
pubmed: 24952903
Nat Rev Mol Cell Biol. 2015 Nov;16(11):643-649
pubmed: 26420232
Cell Death Dis. 2021 May 13;12(5):482
pubmed: 33986254
Nat Rev Cancer. 2006 Nov;6(11):846-56
pubmed: 17060944
Genome Biol. 2014;15(12):554
pubmed: 25476604
Nat Genet. 2011 Aug 28;43(10):1022-5
pubmed: 21874000
Nat Rev Cancer. 2009 Nov;9(11):773-84
pubmed: 19851313
Trials. 2018 Aug 29;19(1):467
pubmed: 30157910
Drugs Aging. 2008;25(11):963-86
pubmed: 18947264
Oxid Med Cell Longev. 2021 Mar 30;2021:6661534
pubmed: 33859780
Nature. 2009 Oct 8;461(7265):762-7
pubmed: 19767730
Mol Cell. 2021 Sep 2;81(17):3526-3541.e8
pubmed: 34186021
Nat Genet. 2011 Jun 05;43(7):668-72
pubmed: 21642991
Sci Rep. 2019 Jun 27;9(1):9354
pubmed: 31249361
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18507-12
pubmed: 19017805
J Bone Miner Res. 2020 Sep;35(9):1676-1684
pubmed: 32488902
Cancer Discov. 2018 Dec;8(12):1548-1565
pubmed: 30322867
N Engl J Med. 2017 Aug 10;377(6):523-533
pubmed: 28578601
Cell Res. 2018 Sep;28(9):934-951
pubmed: 30135474
J Clin Oncol. 2015 Dec 1;33(34):4023-31
pubmed: 26392102
Lung Cancer. 2020 Feb;140:87-92
pubmed: 31901768
PLoS One. 2014 Mar 19;9(3):e92444
pubmed: 24647355
Science. 2019 Apr 19;364(6437):283-285
pubmed: 31000662
Elife. 2021 Dec 30;10:
pubmed: 34967731
Br J Pharmacol. 2009 Jun;157(3):427-35
pubmed: 19371349
Clin Cancer Res. 2018 Jan 1;24(1):84-94
pubmed: 29061644
Lung Cancer. 2012 Jun;76(3):393-6
pubmed: 22197613
Front Oncol. 2020 Feb 18;10:126
pubmed: 32133285
Nature. 2010 May 13;465(7295):243-7
pubmed: 20436459
N Engl J Med. 2018 Aug 23;379(8):753-763
pubmed: 30110579
Lung Cancer (Auckl). 2017 Jun 12;8:39-44
pubmed: 28652837
Nat Genet. 2014 Mar;46(3):225-233
pubmed: 24487277