Preclinical studies have demonstrated that pairing a HIF-2α inhibitor like PT2399 with a CDK4/6 inhibitor produces synergistic anti-tumor effects in ccRCC cell lines and VHL-deficient xenograft models provide a robust rationale for the ongoing investigation of belzutifan and CDK4/6 inhibitors in the treatment of metastatic RCC. The gene discussed is VHL; the disease is nonpapillary renal cell carcinoma.