The key findings were the following: (i) the expression of genes of all three subunits of the DNA-PK complex was increased in human ADPKD transcriptome, as well as localized to cyst lining epithelial cells in human ADPKD; (ii) long-term inhibition of the catalytic activity using specific small molecule inhibitor NU7441 in MDCK 3D cysts reduced MDCK growth by up to 52%; (iii) human ADPKD cells do not exhibit synthetic lethality to DNA-PK inhibition by NU7441; and (iv) finally, the increased sensitivity of human ADPKD cells to TORC1 inhibition was enhanced by combination treatment with NU7441. This evidence concerns the gene CRTC1 and autosomal dominant polycystic kidney disease.