Abstract 1028: Phosphate dysregulation as a novel therapeutic strategy in ovarian and uterine cancers

Abstract Precision medicine promises to improve the treatment of cancer patients, but a lack of therapeutic targets and associated predictive biomarkers limit this reality. To identify novel strategies, we integrate genome-scale CRISPR viability screens across many cancer models with cellular and molecular features to systematically define The Cancer Dependency Map. Using this data, we have identified that XPR1, an inorganic phosphate exporter protein, is a highly selective dependency gene in ovarian and uterine cancers. These cancers are sensitive to loss of XPR1 due to over-expression of SLC34A2, a phosphate importer protein. These data suggest a synthetic lethal relationship in which intracellular phosphate homeostasis is dysregulated in cancer. As proof-of-concept of pharmacological inhibition of XPR1, we have developed protein ligands based on the receptor binding domain of viruses which use XPR1 for cellular entry. These ligands inhibit XPR1 and kill cancer cells in an on-mechanism manner, but may be limited in their clinical utility. As such, we are deepening our understanding of the mechanisms of XPR1-dependent phosphate efflux, and have identified a novel partner protein that is integral to phosphate efflux, possibly revealing functional domains that small molecule inhibitors might target. Overall, these data highlight a novel mechanism to treat cancers by leveraging cancer-specific phosphate dysregulation and further reinforce the Cancer Dependency Map as a powerful engine to uncover novel therapeutic vulnerabilities. Citation Format: Daniel Bondeson, Brenton Paolella, Adhana Asfaw, Michael Rothberg, Thomas Skipper, Gabriel Mesa, Alfredo Gonzalez, Lauren E. Surface, Kentaro Ito, Mariya Kazachkova, William N. Colgan, Allie Warren, Joshua Dempster, J Michael Krill-Burger, Maria Ericsson, Andrew Tang, Iris Fung, Emily S. Chambers, Mai Abdusamad, Nancy Dumont, John Doench, Federica Piccioni, David Root, Jesse Boehm, William C. Hahn, Michael Mannstadt, James McFarland, Francisca Vazquez, Todd Golub. Phosphate dysregulation as a novel therapeutic strategy in ovarian and uterine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1028.