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Nat Cancer DOI:10.1038/s43018-022-00360-7

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

Publication TypeJournal Article
Year of Publication2022
AuthorsBondeson, DP, Paolella, BR, Asfaw, A, Rothberg, MV, Skipper, TA, Langan, C, Mesa, G, Gonzalez, A, Surface, LE, Ito, K, Kazachkova, M, Colgan, WN, Warren, A, Dempster, JM, Krill-Burger, JM, Ericsson, M, Tang, AA, Fung, I, Chambers, ES, Abdusamad, M, Dumont, N, Doench, JG, Piccioni, F, Root, DE, Boehm, J, Hahn, WC, Mannstadt, M, McFarland, JM, Vazquez, F, Golub, TR
JournalNat Cancer
Date Published2022 Apr 18
ISSN2662-1347
Abstract

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.

DOI10.1038/s43018-022-00360-7
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35437317?dopt=Abstract

Alternate JournalNat Cancer
PubMed ID35437317
Grant ListCA212229 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
CA242457 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /