{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T15:39:35Z","timestamp":1789745975111,"version":"4.0.1"},"reference-count":49,"publisher":"American Association for Cancer Research (AACR)","issue":"9","funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["133839-PF-19-203-01-CCG"],"award-info":[{"award-number":["133839-PF-19-203-01-CCG"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 CA215185"],"award-info":[{"award-number":["R01 CA215185"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AR070245"],"award-info":[{"award-number":["R01 AR070245"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100003064","name":"Kidney Cancer Association","doi-asserted-by":"crossref","award":["Advanced Discovery Award"],"award-info":[{"award-number":["Advanced Discovery Award"]}],"id":[{"id":"10.13039\/100003064","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Driven to Cure"}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,9,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This article is featured in Selected Articles from This Issue, p. 1949<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0874","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T09:47:41Z","timestamp":1685526461000},"page":"2072-2089","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8372-3954","authenticated-orcid":false,"given":"Blake R.","family":"Wilde","sequence":"first","affiliation":[{"name":"1Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California."},{"name":"2Jonsson Comprehensive Cancer Center, University of 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