A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors.
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
10 05 2023
10 05 2023
Historique:
received:
01
10
2022
accepted:
27
02
2023
revised:
04
02
2023
medline:
11
5
2023
pubmed:
10
5
2023
entrez:
10
5
2023
Statut:
epublish
Résumé
Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.
Identifiants
pubmed: 37160887
doi: 10.1038/s41392-023-01401-y
pii: 10.1038/s41392-023-01401-y
pmc: PMC10170152
doi:
Substances chimiques
Cisplatin
Q20Q21Q62J
Poly(ADP-ribose) Polymerase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
183Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Informations de copyright
© 2023. The Author(s).
Références
Nucleic Acids Res. 2015 Mar 31;43(6):3154-66
pubmed: 25753674
Nat Chem Biol. 2016 Feb;12(2):109-16
pubmed: 26656090
Exp Cell Res. 2018 May 1;366(1):24-33
pubmed: 29522753
N Engl J Med. 2012 Apr 12;366(15):1382-92
pubmed: 22452356
Cells. 2012 Oct 15;1(4):774-98
pubmed: 24710530
NPJ Syst Biol Appl. 2017 Mar 6;3:8
pubmed: 28649435
Genome Med. 2018 Apr 25;10(1):33
pubmed: 29695279
Transl Oncol. 2017 Apr;10(2):190-196
pubmed: 28182994
Nature. 2018 Jun;558(7709):249-253
pubmed: 29875412
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Mol Cell. 2021 Oct 7;81(19):4008-4025.e7
pubmed: 34508659
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Cell. 2016 Sep 22;167(1):260-274.e22
pubmed: 27641504
Science. 2017 Mar 17;355(6330):1152-1158
pubmed: 28302823
Lancet. 2017 Oct 28;390(10106):1949-1961
pubmed: 28916367
Mol Oncol. 2011 Aug;5(4):387-93
pubmed: 21821475
Mol Cell. 2010 Oct 22;40(2):216-27
pubmed: 20965417
J Mol Cell Biol. 2015 Apr;7(2):92-104
pubmed: 25735597
J Biol Chem. 2012 Jul 13;287(29):24365-77
pubmed: 22645127
Blood. 2010 Nov 25;116(22):4578-87
pubmed: 20739657
Trends Cardiovasc Med. 2018 Feb;28(2):81-90
pubmed: 28869095
BMC Bioinformatics. 2009 Feb 03;10:48
pubmed: 19192299
Clin Cancer Res. 2011 Oct 1;17(19):6356-66
pubmed: 21849418
Mol Cell. 2021 Oct 7;81(19):4026-4040.e8
pubmed: 34624216
Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205
pubmed: 31114916
Nat Commun. 2020 May 26;11(1):2641
pubmed: 32457376
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
N Engl J Med. 2016 Dec;375(22):2154-2164
pubmed: 27717299
Mol Cell Biol. 2011 Dec;31(23):4676-91
pubmed: 21930779
Haematologica. 2020 Feb 20;106(1):185-195
pubmed: 32079692
Nucleic Acids Res. 2017 Jan 4;45(D1):D389-D396
pubmed: 27679477
J Biol Chem. 2010 Apr 16;285(16):12416-25
pubmed: 20159984
J Biol Chem. 2006 Jul 14;281(28):19378-86
pubmed: 16675447
J Biol Chem. 2007 Mar 16;282(11):8052-9
pubmed: 17242401
Cell Rep. 2020 Oct 6;33(1):108221
pubmed: 33027668
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Mol Cell. 2019 Sep 19;75(6):1270-1285.e14
pubmed: 31351877
Mol Cell. 2017 Jul 6;67(1):55-70.e4
pubmed: 28673543
Nat Commun. 2014;5:3361
pubmed: 24553445
Bioinformatics. 2020 Jun 1;36(12):3888-3889
pubmed: 32315385
Mol Cell Proteomics. 2011 Aug;10(8):M110.006148
pubmed: 21536856
Br J Cancer. 2016 Mar 29;114(7):713-5
pubmed: 27022824
Nucleic Acids Res. 2013 Jan;41(Database issue):D955-61
pubmed: 23180760
J Cell Biol. 2000 Mar 20;148(6):1177-86
pubmed: 10725331
Gynecol Oncol. 2016 Nov;143(2):379-388
pubmed: 27614696
BMC Bioinformatics. 2008 Dec 29;9:559
pubmed: 19114008
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Nat Med. 2017 Apr;23(4):461-471
pubmed: 28263311
Nat Genet. 2017 Oct;49(10):1476-1486
pubmed: 28825726
Lancet Oncol. 2014 Jul;15(8):852-61
pubmed: 24882434
Nat Struct Mol Biol. 2010 Jun;17(6):688-95
pubmed: 20453858
EMBO J. 2011 Mar 16;30(6):1067-78
pubmed: 21326211
Eur Urol. 2019 Oct;76(4):452-458
pubmed: 30797618
Cell. 2018 Apr 19;173(3):649-664.e20
pubmed: 29677511