EPAS1 and nonpapillary renal cell carcinoma: It is a peculiarity of this particular cancer that during tumor progression many ccRCCs lose HIF-1α expression and are driven solely by dysregulated HIF-2α expression; this led to the development of belzutifan, a drug that selectively binds to HIF-2α and blocks its dimerization with HIF-1β, thereby causing loss of HIF-2 transcriptional activity and a dramatic therapeutic benefit in patients with advanced ccRCC whose prognosis was previously bleak (11).