Given the role of oncogenic KRAS in cancer initiation and progression and that induction of HIF-1α and HIF-2α is triggered by the majority of mutated oncogenes, or by the loss of essential tumor suppressor genes, the authors generated a series of isogenic HCT116 cell lines defective in either oncogenic KRAS or both HIF-1α and HIF-2α, and subjected them to multiplex genomic, siRNA and high-throughput small-molecule screening. This evidence concerns the gene EPAS1 and cancer.