EPAS1 and nonpapillary renal cell carcinoma: It is however also evident that resistance to HIF-2α inhibitors will become an important clinical challenge as some pre-clinical ccRCC cell line and patient-derived xenograft models are insensitive to HIF-2α inhibitors [6,10] and specific point mutations in HIF-2α or ARNT have been identified that abrogate the inhibitory effects of PT2385 and MK-6482 [9,13].