The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this manuscript. Conflict of Interests: R.B. is a paid member of the scientific advisory board of ApneoTherapeutics and owns equity in the company. C.A.L. is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting GOT1 as a therapeutic approach.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Hypoxia is a hallmark of solid tumors which promotes tumor cell growth, survival, metastasis and confers resistance to chemo and radiotherapies. Targeting hypoxic cells has been difficult. Moreover, inhibitors for the major transcription factors, hypoxia inducible factor (HIF)-1 and HIF-2 have not shown long-term efficacy in most cancers. We have previously shown that HIF-2 is essential for colon tumorigenesis.Using an unbiased screen, we show a significant increase in synthetic lethality of HIF-2 overexpressing tumor enteroids to oxidative cell death activators. The treatment with hypoxia mimetic FG4592 (Roxadustat), led to a robust increase in erastin-, RSL3-, and dimethyl fumarate-induced cell death in a dose-and time-dependent manner. Further, our in-vitro data shows that HIF-2 knock-down cells are completely resistant to these drugs. HIF activation promotes upregulation of lipid synthesis genes in vitro and in vivo leading to oxidative stress. Taken together, our results suggest that this intrinsic sensitivity towards oxidative stress associated with hypoxia could be utilized as a persistent and dynamic form of cell death for colon cancer treatment.