VHL and nonpapillary renal cell carcinoma: However, some VHL–/– ccRCC lines are not affected by manipulations of HIF2α activity (Cho et al, 2016; Stransky et al, 2022), and some VHL-mutant ccRCCs were resistant to HIF2α inhibitor treatment (Choueiri and Kaelin, 2020), suggesting that deficiency of VHL promotes tumor development by yet unidentified and HIF2α-independent mechanisms.