Targeting hypoxia-inducible factor pathways in sporadic and Von Hippel-Lindau syndrome-related kidney cancers

Crit Rev Oncol Hematol. 2022 Aug;176:103750. doi: 10.1016/j.critrevonc.2022.103750. Epub 2022 Jun 18.


Hereditary and sporadic renal cell carcinomas (RCCs) are often associated with Von Hippel-Lindau (VHL)-gene inactivation. Patients with VHL disease have an increased risk of RCC, leading to bilateral nephrectomy and dialysis. In patients with advanced RCC, no standard second-lines are available after progression to immune checkpoint inhibitors (ICIs), and new agents are required to manage progression. HIFs have emerged as a promising target for metastatic RCC patients who have progressed to ICI-based combinations, as well as for those with RCC and VHL syndrome where the goal is to delay surgery and/or and preserve kidney function and avoid dialysis. This review describes the available evidence supporting the use of the small-molecule HIF-2 alpha inhibitor, belzutifan (MK-6482), as well as other new anti-HIF molecules that have demonstrated significant efficacy in VHL disease-related RCCs as well as for sporadic RCC that has progressed after the use of ICI-based combinations.

Keywords: Belzutifan, HIF; Hypoxia inducible factor; Renal cell carcinoma; Von Hippel-Lindau.

Publication types

  • Review

MeSH terms

  • Carcinoma, Renal Cell* / complications
  • Carcinoma, Renal Cell* / drug therapy
  • Humans
  • Hypoxia
  • Kidney Neoplasms* / etiology
  • Kidney Neoplasms* / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • von Hippel-Lindau Disease* / complications
  • von Hippel-Lindau Disease* / genetics


  • Von Hippel-Lindau Tumor Suppressor Protein