A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
21 09 2023
21 09 2023
Historique:
received:
30
05
2023
accepted:
12
09
2023
revised:
06
09
2023
medline:
25
9
2023
pubmed:
22
9
2023
entrez:
22
9
2023
Statut:
epublish
Résumé
Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ~10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients' mutations would improve patients' outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.
Identifiants
pubmed: 37735513
doi: 10.1038/s41419-023-06145-9
pii: 10.1038/s41419-023-06145-9
pmc: PMC10514057
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
BRCA2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
620Subventions
Organisme : NCI NIH HHS
ID : R37 CA249007
Pays : United States
Organisme : NIGMS NIH HHS
ID : T34 GM136469
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA226037
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
Références
Nat Med. 2019 Apr;25(4):628-640
pubmed: 30833752
Front Pharmacol. 2021 Nov 30;12:751568
pubmed: 34916936
Nat Commun. 2022 May 31;13(1):3016
pubmed: 35641523
Sci Rep. 2022 May 11;12(1):7779
pubmed: 35546353
Nature. 2015 Feb 26;518(7540):495-501
pubmed: 25719666
Nat Med. 2019 Apr;25(4):620-627
pubmed: 30833748
Clin Cancer Res. 2014 Feb 1;20(3):540-7
pubmed: 24270682
Cancer Med. 2019 Aug;8(10):4792-4805
pubmed: 31250978
SLAS Discov. 2022 Apr;27(3):159-166
pubmed: 35306207
Front Mol Biosci. 2021 Sep 03;8:728777
pubmed: 34540900
Cells. 2019 Jul 03;8(7):
pubmed: 31277291
Autophagy. 2014 Sep;10(9):1683-4
pubmed: 25046107
Cancer Cell. 2018 Mar 12;33(3):512-526.e8
pubmed: 29533787
Science. 2017 Mar 17;355(6330):1152-1158
pubmed: 28302823
Oncogene. 2019 Nov;38(47):7249-7265
pubmed: 31420604
Mol Cell. 2001 Feb;7(2):263-72
pubmed: 11239455
CA Cancer J Clin. 2022 Jan;72(1):7-33
pubmed: 35020204
Genes Dev. 2007 Nov 15;21(22):2861-73
pubmed: 18006683
Cell Death Dis. 2019 Apr 15;10(5):331
pubmed: 30988278
Cancer Res. 2007 Aug 1;67(15):7078-81
pubmed: 17671173
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Nature. 2008 Feb 28;451(7182):1069-75
pubmed: 18305538
Endocr Relat Cancer. 2018 Jan;25(1):69-82
pubmed: 29066501
Int J Oncol. 2015 Jul;47(1):262-8
pubmed: 25975349
Br J Cancer. 2021 Apr;124(9):1478-1490
pubmed: 33723398
EBioMedicine. 2019 Jun;44:419-430
pubmed: 31126889
Cancers (Basel). 2022 Jun 30;14(13):
pubmed: 35805011
PLoS Comput Biol. 2020 Feb 26;16(2):e1007701
pubmed: 32101536
Cancer Discov. 2018 Mar;8(3):276-287
pubmed: 29317452
Sci Transl Med. 2017 Jul 26;9(400):
pubmed: 28747513
Proc Natl Acad Sci U S A. 2021 Feb 2;118(5):
pubmed: 33495338
Nature. 2010 Dec 23;468(7327):1067-73
pubmed: 20871596
N Engl J Med. 2019 Jul 25;381(4):317-327
pubmed: 31157963
Cell Rep. 2017 Dec 19;21(12):3398-3405
pubmed: 29262321
Cancer Cell. 2017 Aug 14;32(2):185-203.e13
pubmed: 28810144
Cancer Discov. 2016 Feb;6(2):166-75
pubmed: 26658419
Int J Mol Sci. 2021 Oct 14;22(20):
pubmed: 34681760
J Magn Reson Imaging. 2013 Jun;37(6):1499-504
pubmed: 23023925
SLAS Discov. 2019 Mar;24(3):386-397
pubmed: 30682260
Nature. 2012 Mar 28;483(7391):570-5
pubmed: 22460902
Br J Cancer. 2014 Sep 9;111(6):1132-8
pubmed: 25072261
Mol Cell. 2016 Nov 17;64(4):835-849
pubmed: 27818143
Cancer Lett. 2014 Apr 28;346(1):139-47
pubmed: 24378767
SLAS Discov. 2018 Jul;23(6):574-584
pubmed: 29673279
Nat Biotechnol. 2015 Jun;33(6):661-7
pubmed: 25961408
Autophagy. 2023 Apr;19(4):1164-1183
pubmed: 36026492
Bioinformatics. 2016 Sep 15;32(18):2866-8
pubmed: 27153664
Annu Rev Cancer Biol. 2017 Mar;1:19-39
pubmed: 31119201
Minerva Gastroenterol Dietol. 2009 Dec;55(4):445-54
pubmed: 19942828
Nat Med. 2015 Oct;21(10):1163-71
pubmed: 26390243
Cell Death Differ. 2013 Nov;20(11):1444-54
pubmed: 23933813