XPR1, key regulator of phosphate homeostasis and potential drug target for ovarian and lung cancer.

@article{pannier2026xpr1,
  title = {{XPR1, key regulator of phosphate homeostasis and potential drug target for ovarian and lung cancer.}},
  author = {Pascal Pannier and Amel Lebsir and Vincent Ogor and Elycia Calvet and Elodie Chastel and Stéphane D'Agostino and Loreley Calvet and Sukhvinder Sidhu and Anand Kumar and Alexey Rak and Emilia Puig Lombardi and Christophe Marcireau and Isabelle Meaux and Christophe Henry},
  journal = {BMC cancer},
  year = {2026},
  month = jul,
  doi = {10.1186/s12885-026-16624-9},
  url = {https://europepmc.org/article/MED/42928170},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - XPR1, key regulator of phosphate homeostasis and potential drug target for ovarian and lung cancer.
AU  - Pascal Pannier
AU  - Amel Lebsir
AU  - Vincent Ogor
AU  - Elycia Calvet
AU  - Elodie Chastel
AU  - Stéphane D'Agostino
AU  - Loreley Calvet
AU  - Sukhvinder Sidhu
AU  - Anand Kumar
AU  - Alexey Rak
AU  - Emilia Puig Lombardi
AU  - Christophe Marcireau
AU  - Isabelle Meaux
AU  - Christophe Henry
PY  - 2026
DA  - 2026/07/29
JO  - BMC cancer
DO  - 10.1186/s12885-026-16624-9
UR  - https://europepmc.org/article/MED/42928170
AB  - Background  Cancer cells depend heavily on phosphate and its main exporter, XPR1. Therefore, phosphate homeostasis may represent an actionable vulnerability for several indications. In this study, we investigated the molecular mechanisms by which ovarian cell lines are dependent on XPR1 function. We further investigated whether this vulnerability is conserved in lung cancer models, potentially revealing a novel therapeutic target across multiple cancer types.Methods  The functional role of XPR1 was confirmed in a panel of ovarian cell lines. We then broadened the scope of our research by examining lung cancer cell lines that exhibited dysregulated phosphate transporter expression. The mechanistic role of XPR1 was validated through complementary approaches: targeted gene silencing and pharmacological inhibition using an XPR1-specific neutralizing ligand.Results  We demonstrated that PAX8-dependent overexpression of the phosphate transporter SLC34A2 in ovarian cancer (OV) cell lines was associated with impaired phosphate metabolism, and made tumor cells vulnerable to inhibition of XPR1 by gene silencing or a neutralizing ligand (XRBD). Moreover, in vivo conditional knockdown experiments demonstrated that XPR1 gene silencing inhibited tumor growth of an OV cell line-derived xenograft model, and confirmed this synthetic lethal phenotype. To further document the indications that may display susceptibilities towards unbalanced phosphate metabolism, we reviewed public datasets of human cancer. This investigation highlighted frequent genomic or epigenetic alterations of genes encoding several phosphate transporters (including SLC20A1/2 or SLC34A2) in lung and uterine tumors. These observations suggested a vulnerability to XPR1 inhibition. Using in vitro cell models, we demonstrated that genetic silencing of XPR1 or treatment with XRBD impairs cell growth, leading to toxic intracellular phosphate accumulation and cell death in lung cancer cells, characterized by high baseline phosphate import via SLC20A1/2 or SLC34A2 transporters.Conclusion  Our study highlighted a potential therapeutic vulnerability associated with the dysregulation of phosphate homeostasis in ovarian and lung cancers, suggesting XPR1 as a potential target in these indications.
SN  - 1471-2407
ER  -