It is shown that everolimus resistance contributes to a significant increase in the IC50, an elevated percentage of G2/M-phase cells and distinct up-regulation of the cell cycle activating proteins cdk2 and cyclin A. VPA counteracted everolimus resistance by significantly inhibiting tumor growth and reducing cdk2 and cyclin A. Thus, VPA might represent a new promising treatment option for RCC patients with acquired everolimus resistance. Here, CDK2 is linked to neoplasm.