13, 14 For example, previous work in pVHL-defective RCC cell lines that express constitutive HIF-2α has shown that ablation of HIF-2α, either with siRNA or by reintroduction of VHL, increases phosphorylation and accumulation of p53.13, 14 Concordantly, HIF-2α inhibition restored sensitivity to radiation and chemotherapy, suggesting that inhibitors of HIF-2α would be beneficial in combination with radiotherapy, chemotherapeutics or agents that restore p53 pathway activity. This evidence concerns the gene EPAS1 and renal cell carcinoma.