Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer.
Daniel P BondesonBrenton R PaolellaAdhana AsfawMichael V RothbergThomas A SkipperCarly LanganGabriel MesaAlfredo GonzalezLauren E SurfaceKentaro ItoMariya KazachkovaWilliam N ColganAllison WarrenJoshua M DempsterJohn Michael Krill-BurgerMaria EricssonAndrew A TangIris FungEmily S ChambersMai AbdusamadNancy DumontJohn G DoenchFederica PiccioniDavid E RootJesse S BoehmWilliam C HahnMichael MannstadtJames M McFarlandFrancisca VazquezTodd R GolubPublished in: Nature cancer (2022)
Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.
Keyphrases
- copy number
- genome wide
- cell death
- crispr cas
- mitochondrial dna
- cell proliferation
- papillary thyroid
- transcription factor
- climate change
- endothelial cells
- binding protein
- squamous cell
- high throughput
- gene expression
- amino acid
- genome editing
- electronic health record
- machine learning
- high resolution
- young adults
- ionic liquid
- big data
- single cell