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

Abstract

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

Pharmaco-Pheno-Multiomic Integration Reveals Biomarker Profiles and Therapeutic Response Prediction Models in Leukemia and Ovarian Cancer

“…4c). A recent study has shown a vulnerability in ovarian cancer cell lines when XPR1 activity is inhibited when Solute Carrier Family 34 Member 2 (SLC34A2) is overexpressed do to intracellular phosphate overload [20].…”

“…4d). The most strongly linked direct neighbors of the Olaparib response profile include known oncogenes and prognostic markers of ovarian cancer, including Xenotropic And Polytropic Retrovirus Receptor 1 (XPR1) protein expression [20], Notch Receptor 3 (NOTCH3) protein expression [21], MAF BZIP Transcription Factor B (MAFB) RNA expression [22], Argininosuccinate synthetase 1 (ASS1) protein expression [23], and MEIS1 protein expression [24], among others. (Fig.…”