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Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma

Authors :
Andrea Katharina Lindner
Gennadi Tulchiner
Andreas Seeber
Peter J. Siska
Martin Thurnher
Renate Pichler
Source :
Frontiers in Oncology, Vol 12 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

Fumarate hydratase (FH) - deficient renal cell carcinoma (FHdRCC) is a rare aggressive subtype of RCC caused by a germline or sporadic loss-of-function mutation in the FH gene. Here, we summarize how FH deficiency results in the accumulation of fumarate, which in turn leads to activation of hypoxia-inducible factor (HIF) through inhibition of prolyl hydroxylases. HIF promotes tumorigenesis by orchestrating a metabolic switch to glycolysis even under normoxia, a phenomenon well-known as the Warburg effect. HIF activates the transcription of many genes, including vascular endothelial growth factor (VEGF). Crosstalk between HIF and epidermal growth factor receptor (EGFR) has also been described as a tumor-promoting mechanism. In this review we discuss therapeutic options for FHdRCC with a focus on anti-angiogenesis and EGFR-blockade. We also address potential targets that arise within the metabolic escape routes taken by FH-deficient cells for cell growth and survival.

Details

Language :
English
ISSN :
2234943X
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Frontiers in Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.34440c1f4d07413caebd68c900ac80ab
Document Type :
article
Full Text :
https://doi.org/10.3389/fonc.2022.906014