Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC.
Adenocarcinoma
/ metabolism
Antineoplastic Agents
/ analysis
Apoptosis
/ drug effects
Bortezomib
/ pharmacology
Carcinoma, Pancreatic Ductal
/ metabolism
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Pancreatic Neoplasms
/ metabolism
Proteasome Endopeptidase Complex
/ metabolism
Proteostasis
/ drug effects
Proto-Oncogene Proteins c-myc
/ metabolism
Ubiquitin
/ metabolism
MYC
UPR
UPS
apoptosis
pancreatic cancer
proteasome inhibitor
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
04
07
2020
revised:
11
09
2020
accepted:
04
10
2020
pubmed:
26
10
2020
medline:
4
9
2021
entrez:
25
10
2020
Statut:
ppublish
Résumé
The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target; therefore, identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies. First, to identify networks with hyperactive MYC, we profiled transcriptomes of established human cell lines, murine primary PDAC cell lines, and accessed publicly available repositories to analyze transcriptomes of primary human PDAC. Networks active in MYC-hyperactive subtypes were analyzed by gene set enrichment analysis. Next, we performed an unbiased pharmacological screen to define MYC-associated vulnerabilities. Hits were validated by analysis of drug response repositories and genetic gain- and loss-of-function experiments. In these experiments, we discovered that the proteasome inhibitor bortezomib triggers a MYC-associated vulnerability. In addition, by integrating publicly available data, we found the unfolded protein response as a signature connected to MYC. Furthermore, increased sensitivity of MYC-hyperactive PDACs to bortezomib was validated in genetically modified PDAC cells. In sum, we provide evidence that perturbing the ubiquitin-proteasome system (UPS) might be an option to target MYC-hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the UPS as a subtype-specific therapeutic approach.
Identifiants
pubmed: 33099868
doi: 10.1002/1878-0261.12835
pmc: PMC7718946
doi:
Substances chimiques
Antineoplastic Agents
0
Proto-Oncogene Proteins c-myc
0
Ubiquitin
0
Bortezomib
69G8BD63PP
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3048-3064Informations de copyright
© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Oncotarget. 2017 Jul 18;8(29):47490-47496
pubmed: 28537897
Mol Cancer Res. 2019 Sep;17(9):1815-1827
pubmed: 31164413
Nature. 2008 Dec 18;456(7224):971-5
pubmed: 19011615
Nucleic Acids Res. 2015 Jul 1;43(W1):W566-70
pubmed: 25969447
Cell. 2012 Mar 30;149(1):22-35
pubmed: 22464321
Future Oncol. 2014 Aug;10(10):1795-807
pubmed: 25303058
Nat Rev Clin Oncol. 2017 Jul;14(7):417-433
pubmed: 28117417
Leukemia. 2011 Jun;25(6):1026-35
pubmed: 21468039
Oncogene. 2008 Feb 21;27(9):1189-97
pubmed: 17828309
Nat Rev Gastroenterol Hepatol. 2019 Apr;16(4):207-220
pubmed: 30718832
Mol Cancer Ther. 2008 Nov;7(11):3624-31
pubmed: 19001444
Oncogene. 2019 Oct;38(41):6737-6751
pubmed: 31406244
Clin Cancer Res. 2020 Oct 15;26(20):5506-5519
pubmed: 32669378
Blood. 2009 Jul 30;114(5):1046-52
pubmed: 19436050
Nature. 2019 Mar;567(7749):545-549
pubmed: 30894746
Mol Cancer Ther. 2004 Jan;3(1):59-70
pubmed: 14749476
Gastroenterology. 2009 Jul;137(1):361-71, 371.e1-5
pubmed: 19362090
Cancer Cell. 2014 Dec 8;26(6):909-922
pubmed: 25490451
J Clin Invest. 2012 Dec;122(12):4621-34
pubmed: 23143306
Nat Commun. 2017 Nov 23;8(1):1728
pubmed: 29170413
Nature. 2017 Feb 16;542(7641):362-366
pubmed: 28178232
Cancer Cell. 2015 Jul 13;28(1):129-40
pubmed: 26175417
Nucleic Acids Res. 2014;42(16):10433-47
pubmed: 25147211
Cancer Res. 2018 Feb 1;78(3):769-780
pubmed: 29229604
Cell Rep. 2017 Nov 28;21(9):2458-2470
pubmed: 29186684
Genes Dev. 1998 Apr 1;12(7):982-95
pubmed: 9531536
Nat Rev Drug Discov. 2020 Jan;19(1):23-38
pubmed: 31712683
Clin Cancer Res. 2018 Aug 15;24(16):3813-3819
pubmed: 29739787
Front Oncol. 2016 Aug 03;6:181
pubmed: 27536557
Mol Cancer Ther. 2016 Aug;15(8):1792-8
pubmed: 27406986
J Clin Invest. 2018 Apr 2;128(4):1300-1316
pubmed: 29381485
Nat Genet. 2020 Feb;52(2):231-240
pubmed: 31932696
Clin Cancer Res. 2016 Dec 15;22(24):6153-6163
pubmed: 27384421
Nat Cell Biol. 2019 Jan;21(1):54-62
pubmed: 30602769
Pharmacol Rev. 2019 Apr;71(2):170-197
pubmed: 30867233
Oncogene. 2016 Mar 31;35(13):1609-18
pubmed: 26119937
Transl Oncol. 2020 Nov;13(11):100834
pubmed: 32688248
Gut. 2020 Aug;69(8):1472-1482
pubmed: 32001555
Nature. 2015 Feb 26;518(7540):495-501
pubmed: 25719666
Oncogene. 2016 Jul 21;35(29):3880-6
pubmed: 26592448
Cell Death Dis. 2018 Feb 7;9(2):194
pubmed: 29416012
Recent Results Cancer Res. 2016;207:73-91
pubmed: 27557535
Int J Pharm X. 2019 Mar 23;1:100011
pubmed: 31517276
Cancer Res. 2010 Jun 1;70(11):4318-26
pubmed: 20460535
Nat Commun. 2015 Apr 09;6:6744
pubmed: 25855536
Eur J Haematol. 2020 Jul;105(1):35-46
pubmed: 32145111
CA Cancer J Clin. 2019 Jan;69(1):7-34
pubmed: 30620402
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Clin Cancer Res. 2007 May 1;13(9):2811-21
pubmed: 17473215
Cold Spring Harb Perspect Med. 2014 Mar 01;4(3):
pubmed: 24591535
Cancer Discov. 2020 Apr;10(4):588-607
pubmed: 31941709
Database (Oxford). 2017 Jan 1;2017:
pubmed: 29220450
J Clin Invest. 2018 Apr 2;128(4):1283-1299
pubmed: 29480818
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9
pubmed: 12391322
Behav Brain Res. 2001 Nov 1;125(1-2):279-84
pubmed: 11682119
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Cell. 2016 Aug 11;166(4):963-976
pubmed: 27477511
Clin Cancer Res. 2018 Mar 15;24(6):1344-1354
pubmed: 29288237
Trends Cancer. 2016 Jan;2(1):1-3
pubmed: 28741497
PLoS Genet. 2013;9(8):e1003664
pubmed: 23950728
Appl Environ Microbiol. 1996 Feb;62(2):328-31
pubmed: 8593037
Blood. 2007 Oct 1;110(7):2641-9
pubmed: 17525289
Front Oncol. 2019 Jun 05;9:475
pubmed: 31231611
Biochim Biophys Acta Rev Cancer. 2018 Aug;1870(1):43-50
pubmed: 29791870
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4410-7
pubmed: 26216984
Cancer Discov. 2018 Sep;8(9):1112-1129
pubmed: 29853643
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
EMBO Mol Med. 2017 Apr;9(4):482-497
pubmed: 28275007
Biochim Biophys Acta. 2015 May;1849(5):525-43
pubmed: 24657798
Cancer Cell. 2017 Aug 14;32(2):185-203.e13
pubmed: 28810144
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Immunity. 2001 Jan;14(1):45-55
pubmed: 11163229
Ann Oncol. 2005 Oct;16(10):1654-61
pubmed: 16085692
Clin Cancer Res. 2018 Jan 15;24(2):351-359
pubmed: 29101303
Cell Syst. 2018 Mar 28;6(3):282-300.e2
pubmed: 29596783
Biochim Biophys Acta. 2013 Jun;1833(6):1356-66
pubmed: 23485394
Nature. 2018 Feb 1;554(7690):62-68
pubmed: 29364867
Blood Adv. 2019 Jan 8;3(1):51-62
pubmed: 30617217
Nat Med. 2014 Nov;20(11):1340-1347
pubmed: 25326799
Nat Chem Biol. 2013 Sep;9(9):548-56
pubmed: 23892893
BioDrugs. 2019 Oct;33(5):539-553
pubmed: 31392631
Bioinformatics. 2016 May 15;32(10):1502-8
pubmed: 26787660
Nat Med. 2016 Mar;22(3):278-87
pubmed: 26855150
Biol Cell. 2019 Jan;111(1):1-17
pubmed: 30302777
Science. 2012 Jan 20;335(6066):348-53
pubmed: 22157079
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9545-50
pubmed: 22623531
Clin Cancer Res. 2020 Jan 1;26(1):135-146
pubmed: 31481506
Science. 2018 May 18;360(6390):800-805
pubmed: 29622725
Cell. 2016 Jul 28;166(3):740-754
pubmed: 27397505
Clin Cancer Res. 2008 Aug 15;14(16):5116-23
pubmed: 18698029