FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
06 09 2023
06 09 2023
Historique:
received:
05
08
2022
revised:
27
03
2023
accepted:
24
05
2023
pmc-release:
06
03
2024
medline:
7
9
2023
pubmed:
31
5
2023
entrez:
31
5
2023
Statut:
ppublish
Résumé
Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors. This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.
Identifiants
pubmed: 37255402
pii: 727063
doi: 10.1158/2159-8290.CD-22-0874
pmc: PMC10527600
mid: NIHMS1906929
doi:
Substances chimiques
Fumarate Hydratase
EC 4.2.1.2
Purines
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
2072-2089Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR070245
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215185
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
Références
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W652-60
pubmed: 19429898
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Sci Signal. 2021 Jan 05;14(664):
pubmed: 33402335
Metab Eng. 2018 Jan;45:149-157
pubmed: 29191787
Methods Mol Biol. 2011;731:93-103
pubmed: 21516400
Clin Cancer Res. 2021 May 15;27(10):2910-2919
pubmed: 33658299
Nature. 2011 Nov 20;481(7381):385-8
pubmed: 22101431
Nat Genet. 2002 Apr;30(4):406-10
pubmed: 11865300
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Arch Biochem Biophys. 2006 Jun 1;450(1):1-8
pubmed: 16624247
Cell Rep. 2017 Oct 24;21(4):1036-1047
pubmed: 29069586
Fam Cancer. 2014 Dec;13(4):637-44
pubmed: 25012257
Leukemia. 2022 Jul;36(7):1749-1758
pubmed: 35654820
J Biol Chem. 2006 Jun 16;281(24):16768-76
pubmed: 16608839
Leukemia. 2002 Feb;16(2):289-93
pubmed: 11840297
Am J Surg Pathol. 2014 Apr;38(4):567-77
pubmed: 24625422
Cell Rep. 2013 Mar 28;3(3):689-700
pubmed: 23499446
J Pathol. 2011 Sep;225(1):4-11
pubmed: 21630274
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3387-92
pubmed: 11248088
J Intern Med. 2009 Jul;266(1):19-42
pubmed: 19522823
Cancer. 2022 Feb 15;128(4):675-684
pubmed: 34724198
Semin Cell Dev Biol. 2020 Feb;98:15-25
pubmed: 31085323
Free Radic Biol Med. 1999 Nov;27(9-10):922-35
pubmed: 10569625
J Biol Chem. 2014 Aug 29;289(35):24691-9
pubmed: 25028521
Cell. 2012 Feb 17;148(4):639-50
pubmed: 22341439
Hum Mutat. 2020 Jan;41(1):103-109
pubmed: 31444830
J Biol Chem. 1976 Dec 10;251(23):7348-54
pubmed: 1002693
Cancer Cell. 2011 Sep 13;20(3):315-27
pubmed: 21907923
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W71-7
pubmed: 20457745
Nat Rev Nephrol. 2020 Mar;16(3):156-172
pubmed: 31636445
Clin Dysmorphol. 2017 Apr;26(2):117-120
pubmed: 27541980
Cancer Cell. 2011 Oct 18;20(4):524-37
pubmed: 22014577
Cancer Metab. 2013 Mar 21;1(1):12
pubmed: 24280230
Lab Invest. 2021 Oct;101(10):1403-1410
pubmed: 34193963
Sci Rep. 2019 May 20;9(1):7580
pubmed: 31110304
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Genet Med. 2017 Oct;19(10):1105-1117
pubmed: 28492532
J Med Genet. 2023 Jan;60(1):41-47
pubmed: 35121648
Mol Genet Metab. 1998 Apr;63(4):254-62
pubmed: 9635293
Cell Rep. 2017 Sep 26;20(13):3135-3148
pubmed: 28954230
NPJ Precis Oncol. 2018 Mar 20;2:9
pubmed: 29872718
Cell Rep. 2013 May 30;3(5):1440-8
pubmed: 23643539
Adv Enzymol Relat Areas Mol Biol. 1999;73:209-67, xii
pubmed: 10218110
Mol Cell. 2013 Jul 25;51(2):236-48
pubmed: 23747014
Nat Commun. 2015 Jan 23;6:6001
pubmed: 25613188
Cancer Cell. 2011 Oct 18;20(4):511-23
pubmed: 22014576
Clin Cancer Res. 2007 Aug 15;13(16):4667-71
pubmed: 17699843
BMC Bioinformatics. 2010 Jul 23;11:395
pubmed: 20650010