Abstract A009: Therapeutic targeting of P2 × 4 receptor and mitochondrial metabolism in clear cell renal carcinoma

Abstract

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. Large scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in ccRCC expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Seahorse experiments showed that P2XR4 inhibition by 5-BDBD, a potent selective antagonist, caused a rapid dose-dependent reduction of mitochondrial activity and lysosome damage. Moreover, prolonged mitochondrial failure induced by 5-BDBD or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e. opening of the transition pore complex, dissipation of membrane potential and calcium overload), and cell death via both necrosis and apoptosis. P2XR4 pharmacological inhibition was associated with a significant anti-tumor effect both in vitro and in vivo, as shown in ccRCC cell lines, patient-derived organoids and in murine xenografts. Interestingly, higher mitochondrial activity was associated with greater sensitivity to P2XR4 inhibition. Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of renal carcinoma patients. Citation Format: Sabrina Orsi, Christopher Rupert, Roberto Pili, Filomena De Nigris. Therapeutic targeting of P2 × 4 receptor and mitochondrial metabolism in clear cell renal carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr A009.