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

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-...

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Autores principales: Lindner, Andrea Katharina, Tulchiner, Gennadi, Seeber, Andreas, Siska, Peter J., Thurnher, Martin, Pichler, Renate
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337267/
https://www.ncbi.nlm.nih.gov/pubmed/35912170
http://dx.doi.org/10.3389/fonc.2022.906014
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author Lindner, Andrea Katharina
Tulchiner, Gennadi
Seeber, Andreas
Siska, Peter J.
Thurnher, Martin
Pichler, Renate
author_facet Lindner, Andrea Katharina
Tulchiner, Gennadi
Seeber, Andreas
Siska, Peter J.
Thurnher, Martin
Pichler, Renate
author_sort Lindner, Andrea Katharina
collection PubMed
description 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.
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spelling pubmed-93372672022-07-30 Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma Lindner, Andrea Katharina Tulchiner, Gennadi Seeber, Andreas Siska, Peter J. Thurnher, Martin Pichler, Renate Front Oncol Oncology 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. Frontiers Media S.A. 2022-07-15 /pmc/articles/PMC9337267/ /pubmed/35912170 http://dx.doi.org/10.3389/fonc.2022.906014 Text en Copyright © 2022 Lindner, Tulchiner, Seeber, Siska, Thurnher and Pichler https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Lindner, Andrea Katharina
Tulchiner, Gennadi
Seeber, Andreas
Siska, Peter J.
Thurnher, Martin
Pichler, Renate
Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title_full Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title_fullStr Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title_full_unstemmed Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title_short Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
title_sort targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337267/
https://www.ncbi.nlm.nih.gov/pubmed/35912170
http://dx.doi.org/10.3389/fonc.2022.906014
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