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Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer.
Bondeson, Daniel P; Paolella, Brenton R; Asfaw, Adhana; Rothberg, Michael V; Skipper, Thomas A; Langan, Carly; Mesa, Gabriel; Gonzalez, Alfredo; Surface, Lauren E; Ito, Kentaro; Kazachkova, Mariya; Colgan, William N; Warren, Allison; Dempster, Joshua M; Krill-Burger, John M; Ericsson, Maria; Tang, Andrew A; Fung, Iris; Chambers, Emily S; Abdusamad, Mai; Dumont, Nancy; Doench, John G; Piccioni, Federica; Root, David E; Boehm, Jesse; Hahn, William C; Mannstadt, Michael; McFarland, James M; Vazquez, Francisca; Golub, Todd R.
Affiliation
  • Bondeson DP; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Paolella BR; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Asfaw A; Merck Research Laboratories, Cambridge, MA, USA.
  • Rothberg MV; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Skipper TA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Langan C; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Mesa G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gonzalez A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Surface LE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ito K; Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Kazachkova M; Harvard Medical School, Boston, MA, USA.
  • Colgan WN; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Warren A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Dempster JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Krill-Burger JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ericsson M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tang AA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fung I; Harvard Medical School, Boston, MA, USA.
  • Chambers ES; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Abdusamad M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Dumont N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Piccioni F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Root DE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Boehm J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hahn WC; Merck Research Laboratories, Cambridge, MA, USA.
  • Mannstadt M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • McFarland JM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Vazquez F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Golub TR; Harvard Medical School, Boston, MA, USA.
Nat Cancer ; 3(6): 681-695, 2022 06.
Article in En | MEDLINE | ID: mdl-35437317
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Membrane Proteins / Nerve Tissue Proteins Limits: Female / Humans Language: En Journal: Nat Cancer Year: 2022 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Membrane Proteins / Nerve Tissue Proteins Limits: Female / Humans Language: En Journal: Nat Cancer Year: 2022 Document type: Article Affiliation country: United States