PDZ domain containing 1 sensitizes renal cancer cells to everolimus via inhibiting phosphatase and tensin homolog phosphorylation-mediated mTOR pathway activation.

Abstract

Aberrant activation of the phosphatase and tensin homolog (PTEN)-PI3K/AKT/mTOR pathway is a key driver of renal cell carcinoma (RCC) progression, making mTOR inhibition with everolimus a critical therapeutic strategy. However, the mechanisms driving mTOR pathway activation and the emergence of drug resistance remain poorly understood. In this study, we found that phosphorylated PTEN (pPTEN at S380/T382/T383) level was increased in RCC. Increased pPTEN level was associated with impaired suppression of mTOR pathway activation, and was accompanied by RCC progression and resistance to everolimus. Conversely, inhibition of PTEN phosphorylation restored PTEN function, reducing tumor growth and restoring sensitivity to everolimus. Further investigation revealed that downregulation of PDZ domain-containing 1 (PDZK1) in RCC tissues increased pPTEN level, resulting in mTOR pathway activation. PDZK1 was found to inhibit RCC malignancy by preventing PTEN phosphorylation and mTOR activation. Moreover, PDZK1 overexpression sensitized RCC cells to everolimus across cell, animal and organoid models. In conclusion, our findings indicate that PDZK1 downregulation in RCC cells contributes to pPTEN accumulation, mTOR pathway activation, and everolimus resistance. This highlights the PDZK1-pPTEN axis as a potential therapeutic target in RCC, suggesting that modulating PDZK1 or PTEN phosphorylation could enhance the efficacy of everolimus treatment.