Dynamic inositol pyrophosphate synthesis is a targetable therapeutic opportunity in ovarian cancer.
We previously reported that the phosphate exporter XPR1 is required to prevent toxic phosphate accumulation in ovarian cancer cells. To guide therapeutic development, we sought to systematically compare potential strategies to inhibit XPR1: directly targeting the phosphate efflux channel, targeting its partner protein KIDINS220, or inhibiting the synthesis of inositol pyrophosphates (PP-InsPs),…
Researchers have found that targeting the phosphate exporter XPR1 in ovarian cancer cells could lead to a new therapeutic approach. Previous research identified that XPR1 is responsible for preventing toxic phosphate accumulation within these cells. To explore potential strategies to inhibit XPR1, scientists systematically compared different methods.
They discovered that loss of function mutations in XPR1 occurred in specific regions of the protein, with the most detrimental mutations found in the PP-InsP-binding domain. On the other hand, mutations in KIDINS220, another protein involved with XPR1, were less frequent and altered XPR1 localization, suggesting KIDINS220's role as a scaffolding molecule.
The study confirmed that inhibiting inositol pyrophosphate (PP-InsP) synthesis using IP6K inhibitors had a similar effect to blocking XPR1. IP6K inhibition replicated XPR1 inhibition across numerous cancer cell lines, with the sensitivity solely due to the inhibition of cellular phosphate efflux. Additionally, researchers observed that IP6K inhibitors reduced tumor growth in ovarian cancer xenograft models, although high exposures were necessary to achieve efficacy due to the rapid resynthesis of PP-InsPs.
This comprehensive evaluation of the XPR1-dependent phosphate efflux network supports the idea of directly targeting XPR1 as a precision medicine strategy for ovarian cancer patients.
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