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Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factor hypoxia-inducible factor (HIF)-1α and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult and tumors rapidly acquire resistance to recently developed inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α expressing tumor enteroids. Our work demonstrates that HIF-2α integrates two independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upreguated lipid and iron regulatory genes in colon cancer cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Secondly, via an iron dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS, via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrate a mechanistic vulnerability in cancer cells that were the dependent on HIF-2α that can be leveraged for colon cancer treatment.

HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron