FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer.
Blake R WildeNishma ChakrabortyNedas MatulionisStephanie HernandezDaiki UenoMichayla E GeeEdward D EsplinKaren OuyangKeith NykampBrian M ShuchHeather R ChristofkPublished in: Cancer discovery (2023)
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 pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
Keyphrases
- papillary thyroid
- copy number
- squamous cell
- end stage renal disease
- genome wide
- biofilm formation
- childhood cancer
- ejection fraction
- chronic kidney disease
- induced apoptosis
- gene expression
- newly diagnosed
- climate change
- peritoneal dialysis
- dna methylation
- pseudomonas aeruginosa
- lymph node metastasis
- signaling pathway
- escherichia coli
- cell therapy
- cell cycle arrest
- staphylococcus aureus
- crystal structure
- bone marrow
- candida albicans