Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia‐inducible factors HIF 1α and HIF 2α

Summary Chemotherapy resistance is a major contributor to poor treatment responses and tumour relapse, the development of which has been strongly linked to the action of cancer stem cells ( CSC s). Mounting evidence suggests that CSC s are reliant on low oxygen conditions and hypoxia‐inducible factors 1α and 2α ( HIF 1α and HIF 2α) to maintain their stem cell features. Research in the last decade has begun to clarify the functional differences between the two HIF α subtypes ( HIF αs). Here, we review and discuss these differences in relation to CSC ‐associated drug resistance. Both HIF αs contribute to CSC survival but play different roles – HIF 1α being more responsible for survival functions and HIF 2α for stemness traits such as self‐renewal – and are sensitive to different degrees of hypoxia. Failure to account for physiologically relevant oxygen concentrations in many studies may influence the current understanding of the roles of HIF αs. We also discuss how hypoxia and HIF αs contribute to CSC drug resistance via promotion of ABC drug transporters Breast cancer resistance protein ( BCRP ), MDR 1, and MRP 1 and through maintenance of quiescence. Additionally, we explore the PI 3K/ AKT cell survival pathway that may support refractory cancer by promoting CSC s and activating both HIF 1α and HIF 2α. Accordingly, HIF 1α and HIF 2α inhibition, potentially via PI 3K/ AKT inhibitors, could reduce chemotherapy resistance and prevent cancer relapse.