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首页> 外文期刊>Endocrine Reviews >Hypoxia-Inducible Factor 2 Alpha (HIF2 alpha) Inhibitors: Targeting Genetically Driven Tumor Hypoxia
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Hypoxia-Inducible Factor 2 Alpha (HIF2 alpha) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

机译：Hypoxia-Inducible Factor 2 Alpha (HIF2 alpha) Inhibitors: Targeting Genetically Driven Tumor Hypoxia

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摘要

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.

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