Pharmacologic Targeting of TFIIH Suppresses KRAS-Mutant Pancreatic Ductal Adenocarcinoma and Synergizes with TRAIL.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
16 09 2022
16 09 2022
Historique:
received:
10
12
2021
revised:
26
04
2022
accepted:
05
07
2022
pubmed:
13
7
2022
medline:
20
9
2022
entrez:
12
7
2022
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next-generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS-mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TRAIL, effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy, with direct translational implications for current clinical trials on metastatic pancreatic cancer patients.
Significance:
This study utilizes functional genetic and pharmacological profiling of KRAS-mutant pancreatic adenocarcinoma to identify therapeutic strategies and finds that TFIIH inhibition synergizes with TRAIL to induce apoptosis in KRAS-driven pancreatic cancer.
Identifiants
pubmed: 35819261
pii: 706975
doi: 10.1158/0008-5472.CAN-21-4222
pmc: PMC9481717
mid: NIHMS1824688
doi:
Substances chimiques
KRAS protein, human
0
Cyclin-Dependent Kinases
EC 2.7.11.22
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3375-3393Subventions
Organisme : NCI NIH HHS
ID : U01 CA224012
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA214428
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217883
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA186241
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA124435
Pays : United States
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
©2022 American Association for Cancer Research.
Références
Cell Death Differ. 2014 Mar;21(3):491-502
pubmed: 24362439
Nat Biotechnol. 2013 Mar;31(3):213-9
pubmed: 23396013
Oncologist. 2017 Dec;22(12):1424-1426
pubmed: 28982802
PLoS Med. 2009 Apr 7;6(4):e1000046
pubmed: 19360088
Genes Dev. 2000 Aug 15;14(16):2060-71
pubmed: 10950869
Gastroenterology. 2016 Jul;151(1):180-193.e12
pubmed: 27003603
Elife. 2019 Mar 12;8:
pubmed: 30860024
Nat Rev Mol Cell Biol. 2012 May 10;13(6):343-54
pubmed: 22572993
Biochem Biophys Res Commun. 2003 Feb 21;301(4):1038-44
pubmed: 12589817
Sci Transl Med. 2012 Oct 17;4(156):156ra139
pubmed: 23076356
Angew Chem Int Ed Engl. 2015 Feb 2;54(6):1859-63
pubmed: 25504624
Lancet Oncol. 2020 Apr;21(4):508-518
pubmed: 32135080
J Med Chem. 2004 Mar 25;47(7):1719-28
pubmed: 15027863
Nat Chem Biol. 2016 Oct;12(10):876-84
pubmed: 27571479
Gut. 2015 Nov;64(11):1783-9
pubmed: 25636698
J Biol Chem. 2016 May 27;291(22):11843-51
pubmed: 27053107
Cell Death Differ. 2011 Mar;18(3):538-48
pubmed: 21072056
Mol Cell. 2003 Mar;11(3):577-90
pubmed: 12667443
Nat Protoc. 2013 Dec;8(12):2471-82
pubmed: 24232249
Nat Cancer. 2021 Jan;2(1):49-65
pubmed: 35121887
CA Cancer J Clin. 2018 Jan;68(1):7-30
pubmed: 29313949
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Oncogene. 2009 Dec 17;28(50):4409-20
pubmed: 19767776
Nature. 2017 Nov 23;551(7681):512-516
pubmed: 29132146
N Engl J Med. 2011 May 12;364(19):1817-25
pubmed: 21561347
Nature. 2015 Feb 26;518(7540):495-501
pubmed: 25719666
Nat Med. 2017 Jun;23(6):703-713
pubmed: 28481359
J Clin Invest. 1999 Jul;104(2):155-62
pubmed: 10411544
Nat Commun. 2017 Feb 21;8:14294
pubmed: 28220783
Nat Genet. 2017 Mar;49(3):358-366
pubmed: 28092682
Nat Med. 2016 May;22(5):497-505
pubmed: 27089513
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Clin Cancer Res. 2017 Apr 1;23(7):1638-1646
pubmed: 28373362
Cancer Discov. 2020 Apr;10(4):588-607
pubmed: 31941709
Nat Rev Dis Primers. 2016 Apr 21;2:16022
pubmed: 27158978
J Clin Invest. 2012 Feb;122(2):639-53
pubmed: 22232209
Clin Cancer Res. 2018 Jun 15;24(12):2828-2843
pubmed: 29599409
Nat Med. 1999 Feb;5(2):157-63
pubmed: 9930862
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
J Clin Oncol. 2019 Oct 10;37(29):2643-2650
pubmed: 31398082
J Am Chem Soc. 1972 Oct 4;94(20):7194-5
pubmed: 5072337
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Rev Cancer. 2013 May;13(5):299-314
pubmed: 23612459
Nat Struct Mol Biol. 2012 Nov;19(11):1108-15
pubmed: 23064645
Blood. 2009 May 7;113(19):4637-45
pubmed: 19234140
Gastroenterology. 2015 Dec;149(7):1932-1943.e9
pubmed: 26255562
N Engl J Med. 2019 Jul 25;381(4):317-327
pubmed: 31157963
Cell Rep. 2016 Jan 12;14(2):320-31
pubmed: 26748711
Nat Cancer. 2020 Jan;1(1):59-74
pubmed: 35118421
Cell. 2017 Feb 9;168(4):629-643
pubmed: 28187285
J Gastrointest Surg. 2000 Nov-Dec;4(6):567-79
pubmed: 11307091
Clin Cancer Res. 2012 Nov 15;18(22):6339-47
pubmed: 22991414
J Biomol Screen. 2008 Feb;13(2):149-58
pubmed: 18216396
Nature. 2014 Jul 31;511(7511):616-20
pubmed: 25043025
Cancer J Sci Am. 1998 May-Jun;4(3):194-203
pubmed: 9612602
Chem Rev. 2013 Nov 13;113(11):8456-90
pubmed: 23952966
J Clin Oncol. 1997 Jun;15(6):2403-13
pubmed: 9196156
Nat Chem Biol. 2011 Mar;7(3):182-8
pubmed: 21278739
J Cell Sci. 2005 Nov 15;118(Pt 22):5171-80
pubmed: 16280550
Clin Cancer Res. 2017 Apr 1;23(7):1647-1655
pubmed: 28373363
Gastroenterology. 2021 Jan;160(1):362-377.e13
pubmed: 33039466
Gut. 2018 Dec;67(12):2142-2155
pubmed: 29080858
Genome Res. 2012 Mar;22(3):568-76
pubmed: 22300766
Nat Rev Cancer. 2017 May 24;17(6):352-366
pubmed: 28536452
Cancer Res. 2021 Jun 15;81(12):3402-3414
pubmed: 33687950
Annu Rev Biochem. 2016 Jun 2;85:265-90
pubmed: 27294439
Nat Methods. 2009 Aug;6(8):569-75
pubmed: 19644458
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9545-50
pubmed: 22623531
N Engl J Med. 2013 Oct 31;369(18):1691-703
pubmed: 24131140
Clin Cancer Res. 2014 Aug 15;20(16):4274-88
pubmed: 25125259
Br J Cancer. 2017 Aug 8;117(4):572-582
pubmed: 28720843
Gut. 2011 Feb;60(2):225-37
pubmed: 20876774