Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies

Abstract

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4-6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance.

Keywords: HIF-2α targeting; VHL tumor; belzutifan; renal cell carcinoma.

Figure 1

The role of HIFs in renal tumor development. The figure illustrates the involvement of HIFs in the pathogenesis of RCC. HIFs are key transcription factors activated under hypoxic conditions and are commonly dysregulated in RCC due to mutations in the VHL tumor suppressor gene. In normal oxygen levels, VHL targets HIF for proteasomal degradation. In RCC, the loss of VHL function leads to constitutive stabilization of the HIF-α subunit that accumulates and translocates to the nucleus and binds to HIF-β, forming an active transcriptional complex. This HIF complex binds to hypoxia-responsive elements (HREs) within the promoter regions of hypoxia-related genes, activating a broad transcriptional program that includes genes regulating angiogenesis, metabolism, erythropoiesis, and cell survival. Hypoxia-inducible factors (HIFs); renal cell carcinoma (RCC); von Hippel–Lindau (VHL).

Figure 2

Belzutifan inhibits hypoxia-inducible factor-2 alpha (HIF-2α), a key transcription factor involved in cellular adaptation to hypoxia. By targeting HIF-2α, belzutifan disrupts tumor growth and survival pathways in hypoxia-driven cancers.