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Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer

Daniel P Bondeson1, Brenton R Paolella1,2, Adhana Asfaw1

  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nature Cancer
|April 19, 2022
PubMed

Insights

Researchers identified a new therapeutic target for ovarian cancer. Overexpression of the phosphate importer SLC34A2 makes cancer cells sensitive to the loss of phosphate exporter XPR1, leading to toxic phosphate buildup and cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Clinical outcomes for ovarian and uterine cancers remain poor despite precision medicine advances.
  • Frequent overexpression of the phosphate importer SLC34A2 is observed in cancer cells.

Purpose of the Study:

  • To identify novel therapeutic vulnerabilities in ovarian and uterine cancers.
  • To investigate the role of phosphate transport in cancer cell survival.

Main Methods:

  • Genome-scale CRISPR-Cas9 loss-of-function screens in 851 human cancer cell lines.
  • In vitro and in vivo validation of SLC34A2 and XPR1 interactions.
  • Analysis of patient-derived tumor samples for gene expression and copy number alterations.

Main Results:

  • Overexpression of SLC34A2 correlates with sensitivity to XPR1 loss.
  • PAX8-dependent SLC34A2 overexpression and XPR1 amplification/overexpression found in patient tumors.
  • Inhibition of XPR1 leads to toxic intracellular phosphate accumulation in SLC34A2-high cells.
  • XPR1 interacts with KIDINS220, and disruption causes cell death.

Conclusions:

  • The XPR1-KIDINS220 complex and phosphate dysregulation represent a therapeutic vulnerability in ovarian cancer.
  • Targeting phosphate transport offers a potential new strategy for treating these cancers.

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