Abstract 1542 Dysregulated phosphate homeostasis as precision cancer medicine

Inorganic phosphate is a crucial nutrient for all of life, from the backbone of nucleic acids to key posttranslational modifications. Although the physiological endocrine networks to regulate phosphate at an organismal level are well defined, how individual cells sense, store, and regulate phosphate is poorly understood. Despite its ubiquity, we have previously shown that inhibiting the phosphate exporter XPR1 can selectively kill certain cancers which overexpress phosphate importers. Using a saturating mutagenesis approach to identify druggable domains on XPR1, we find that the SPX domain – regulated by inositol pyrophosphates – is crucial for activity. Pharmacological depletion of inositol pyrophosphates inhibits XPR1, which leads to intracellular phosphate accumulation and cell death. Together, these studies reveal novel mechanisms of cellular phosphate homeostasis and highlight phosphate dysregulation as a potential therapeutic strategy to treat cancer. National Cancer Institute.