Inactivation from the VHL tumor suppressor gene may be the signature initiating event in obvious cell kidney cell carcinoma (ccRCC), the most typical type of kidney cancer, and results in the buildup of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors work well in certain ccRCC cases, but both de novo and purchased resistance happen to be noticed in the laboratory as well as in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in 2 species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally caused the CDK4/6 partner cyclin D1, HIF-2α wasn’t needed for that elevated CDK4/6 dependence on VHL-/- ccRCC cells. Accordingly, the antiproliferative results of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- ccRCC cells and never hostile with HIF-2α inhibition in HIF-2α-independent cells. These bits of information support testing CDK4/6 inhibitors as treating ccRCC, alone and in conjunction with HIF-2α inhibitors.PT2399