Hypoxia-Inducible Factor 2 Alpha (HIF2α) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

Tumors driven by deficiency of the VHL gene product, which is involved in degradation of the hypoxia-inducible factor subunit 2 alpha (HIF2 alpha), are natural candidates for targeted inhibition of this pathway. Belzutifan, a highly specific and well-tolerated HIF2 alpha inhibitor, recently received FDA approval for the treatment of nonmetastatic renal cell carcinomas, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas from patients with von Hippel-Lindau disease, who carry VHL germline mutations. Such approval is a milestone in oncology; however, the full potential, and limitations, of HIF2 alpha inhibition in the clinic are just starting to be explored. Here we briefly recapitulate the molecular rationale for HIF2 alpha blockade in tumors and review available preclinical and clinical data, elaborating on mutations that might be particularly sensitive to this approach. We also outline some emerging mechanisms of intrinsic and acquired resistance to HIF2 alpha inhibitors, including acquired mutations of the gatekeeper pocket of HIF2 alpha and its interacting partner ARNT. Lastly, we propose that the high efficacy of belzutifan observed in tumors with genetically driven hypoxia caused by VHL mutations suggests that a focus on other mutations that similarly lead to HIF2 alpha stabilization, such as those occurring in neuroendocrine tumors with disruptions in the tricarboxylic acid cycle (SDHA/B/C/D, FH, MDH2, IDH2), HIF hydroxylases (EGLN/PHDs), and the HIF2 alpha-encoding gene, EPAS1, are warranted.

Automated summary

The HIF2 alpha inhibitor belzutifan has been approved by the FDA as a treatment for certain tumors, opening up a new approach in cancer therapy. This article reviews the molecular rationale and clinical data for HIF2 alpha blockade, as well as discussing potential mutations that may be sensitive to this approach. Resistance mechanisms to HIF2 alpha inhibitors, including acquired mutations in HIF2 alpha and its interacting partner ARNT, are also outlined. The high efficacy of belzutifan in tumors driven by genetic hypoxia suggests that other mutations leading to HIF2 alpha stabilization should be further investigated.