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- W4386469934 abstract "<div>Abstract<p>Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline <i>FH</i> 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 <i>FH</i> 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 <i>de novo</i> 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 <i>in vivo</i>. These findings suggest the pathogenicity of patient-associated <i>FH</i> variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.</p>Significance:<p>This study functionally characterizes patient-associated <i>FH</i> 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.</p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-9-ITI target=_blank>This article is featured in Selected Articles from This Issue, p. 1949</a></i></p></div>" @default.
- W4386469934 created "2023-09-07" @default.
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- W4386469934 date "2023-09-06" @default.
- W4386469934 modified "2023-09-27" @default.
- W4386469934 title "Data from FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer" @default.
- W4386469934 doi "https://doi.org/10.1158/2159-8290.c.6762488.v2" @default.
- W4386469934 hasPublicationYear "2023" @default.
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